KR890001489B1 - Process for the preparation of 1-oxa-1-dethia-cephalosporin derivatives and new intermediates compounds therefor - Google Patents

Abstract

7-Acylamino-2-alkyl-1-oxa-1-dethia-3-cephem derivs. of formula (I) and their salts and esters are new. In (I), R is R1CH(R2)-[R1=2- or 3-thienyl; R2=H or carboxyl or a gp. of formula (II)[R3=H, lower alkyl or carboxyl lower alkyl; R4 is H or methoxy; R5 is lower alkyl; R6 is tetrazolyl thiomethyl or methylterazolyl thiomethyl. (I) are useful as broad spectrum antibacterials.

Description

1-oxa-1-decia-cephalosporin derivative and method for preparing the intermediate compound

The present invention relates to novel 1-oxa-1-dethia-cephalosporin derivatives and to pharmaceutically acceptable salts and esters thereof which are useful as antibacterial agents.

More specifically, the present invention relates to a novel 7-acylamino-1-oxa-1-dethia-3-cepem derivative having a lower alkyl substituent at the 2-position of its cephem nucleus and such pharmaceutically acceptable. It relates to salts and esters of the novel 7-acylamino-1-oxa-1-dethia-3-cepem derivatives.

The present invention also relates to a process for producing such a new 7-acylamino-2-alkyl-1-oxa-1-decia-3-cefem derivative.

In addition, the present invention provides a novel 7β-imino- useful as an intermediate product used as a starting compound in the preparation of the above 7-acylamino-2-alkyl-1-oxa-1-dethia-3-cepem derivatives and their homologues. It relates to a 2-alkyl-1-oxa-1-dethia-cephalosporin compound.

The present invention also relates to a method for producing such a new intermediate, 7β-amino-2-alkyl-1-oxa-1-decia-cephalosporin compound.

In recent years, considerable research has been conducted on the synthesis of various derivatives of 1-oxa-1-dethia-3-cepem compounds.

(See Japanese Patent Laid-Open No. 78-25551).

The inventors have succeeded in the preparation of 2-alkyl-substituted derivatives of 1-oxa-1-decia-3-cepem compounds as new compounds and their corresponding 1-oxa-1-decia- free of 2-alkyl substituents. It was found to be more resistant to β-lactamase and to higher antibacterial activity than 3-cefem compounds.

Firstly, the present invention provides 2-alkyl-1-oxa-dethia-cephalosporin derivatives of the following general formula (I) and pharmaceutically acceptable salts or esters thereof.

Where R represents a group of the general formula

In the above formula, R ₁ is a 2-thienyl or 3-thienyl group, R ₂ is a hydrogen atom or a carboxyl group: or a group of the following general formula.

In the above formula, R ₃ is a hydrogen atom, a lower alkyl group or a carboxyl lower alkyl group.

R ₄ is a hydrogen atom or a methoxy group, R ₅ is a lower alkyl group, in particular a methyl group, and R ₆ is a thiomethyl group having a heterocyclic ring and the formula-CH ₂ -S-Het wherein Het is substituted or unsubstituted. It is a heterocyclic group.)

A representative example of R ₆ is tetrazolyl-thiomethyl or methyltetrazolyl thiomethyl group in formula (I).

A "lower alkyl" group in formula (I) is an alkyl group of C ₁ -C ₄ . The lower alkyl group of R ₅ may have a steric configuration of α or β, and a methyl group is preferable in the α-configuration or β-configuration.

Heterocyclic thiomethyl group of R ₆ -heterocyclic group in CH ₂ -S-Het Het is a 5-membered heterocyclic group having heteroatoms such as nitrogen, oxygen or sulfur, and Het is preferably a tetrazolyl, triazolyl or thiazolyl group Do.

Substituents present in the heterocyclic group (Het) include a lower alkyl group or a carboxy alkyl group, and are groups that can be commonly used as a trisubstituted group of known cephalosporins.

Pharmaceutically acceptable salts of the new compounds of general formula (I) include the carboxyl groups and bases present in the compounds, in particular their salts and inorganic bases, such as sodium or potassium salts and alkaline earth metal salts such as calcium, magnesium or zinc salts. : Addition salts and basic amino acids such as lysine, arginine, ornithine or histidine: Conventional non-toxic salts which can be produced by reacting the addition salts with organic amine salts or other basic salts forming salts with cephalosporins ( Carboxylate).

Other non-toxic salts of the new compound (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; Salts produced by addition to organic or acidic amino acids such as tricarboxylic acid, benzenesulfonic acid, methanesulfonic acid, maleic acid, tartaric acid or P-toluenesulfonic acid, or acidic amino acids such as sulfonic acid and glutamic acid, or other basic groups, are included.

Moreover, these salts include intermolecular salt or intramolecular salt.

Nontoxic esters of this new compound (I) are esters of carboxyl groups present in the latter (intramolecular or molecular acid salts) with pharmaceutically acceptable ester forming groups. Among these esters, unstable esters with ester forming groups that can be separated upon hydrolysis in vivo are preferred.

Examples of the ester forming group are acetoxymethyl groups. Pivaloyloxymethyl group and the (alpha) -ethoxycarbonyloxyethyl group. Aliphatic or aromatic groups such as phthalyl group and phenyl group.

Representative examples of the novel sulfide (I) according to the present invention include the following compounds.

The compound numbers listed above are used in Table 1 below.

The new compound (I) of the present invention is distinctly different from each Cempe derivatives of Japanese Patent Application Laid-Open No. 78-25551 with respect to the presence of a lower alkyl group at the 2-position of the cephem nucleus.

In addition, the novel compounds of the present invention have great significance for improving antibacterial properties.

The minimum inhibitory concentrations (M.I.C) (mcg / ml) of this compound (I) and various bacteria are shown in Table 1 below.

As shown in Table 1, the new compound (I) of the present invention has high activity against Gram-positive bacteria and Gram-negative bacteria.

Thus, these compounds (I) act as useful antibiotics.

TABLE 1

As shown in the previous table, the compound of Ilva formula (I) according to the present invention exhibits excellent properties as an antimicrobial agent, and can be orally or parenterally administered to the therapeutic or prophylactic treatment of bacterial hepatitis in mammals including humans. It is a useful antibiotic.

Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by the following methods.

That is, the 7-amino group of the 2-alkyl-7-amino-1-oxa-1-decia-cepem compound of the following general formula (II) is obtained by condensation (or acylate) with the carboxylic acid of the following formula (III) It can be prepared by leaving the protecting group (A ') in the 7-N-acylated product.

Wherein R ₄ , R ₅ and R ₆ are as described above, A 'is a carboxyl protecting group such as phenylmethyl or diphenylmethyl group, R is as described above, acid chloride or active ester, etc. It is a functional derivative of carboxylic acid.

Secondly, the present invention provides a 2-alkyl-7-amino-1-oxa-1-decia-3-cepem compound of the following general formula (II) in an inert organic solvent under anhydrous state, Acylating with an acid yields the 7-N-acylated product of the following general formula (I ') and then leaves the carboxyl protecting group (A') from the 7-N-acylated product of the following general formula (I ') Provided is a process for the preparation of 7-acylamino-2-alkyl-1-oxa-1-dethia-3-cepem derivatives of general formula (I).

Wherein R ₄ , R ₅ and R ₆ are as described above, A 'is a carboxy protecting group, R is as described above and is a functional derivative of carboxylic acid.

The carboxylic acid reagent of the general formula (III) is thienyl-substituted carboxylic acid of the following general formula (III ') or an acid halide, an acid anhydride, a mixed acid anhydride, an active ester or an active azide of the above carboxylic acid. .

In the above formula, R ₂ is the same as described above.

The carboxylic acid reagent of the general chamber (III) is also a thiazolyl-substituted carboxylic acid of the following general formula (III ″) or an acid halide, acid anhydride, mixed acid anhydride, active ester or active azide of the above carboxylic acid. .

R ₃ is as described above.

Condensation or acylation of the 7-amino group of the starting compound of formula (II) with the carboxylic acid of formula (III) can be carried out by a known amidation method used for the synthesis of general β-lactam compounds. .

Thus, for example, "carbodiimide" treatment is preferably used for direct condensation with carboxylic acid (III). The acylation reaction is a conventional "acid known to produce amides using functional derivatives of carboxylic acid (III) such as acid halides, active esters, active azides, acid anhydrides or mixed acid anhydrides of carboxylic acid (III). It can be normally carried out by the "halide production method", the active ester production method "or the" mixed acid anhydride production method ".

The reaction temperature that can be used is not limited, but the reflux temperature used as the reaction medium at room temperature is preferable.

In general, however, the reaction must be carried out in a mild state, for example cooling or gentle heating.

The carboxyl protecting group (A ′) in the 4-carboxyl group of the starting material of general formula (II) is a conventional protecting group used in this field, for example, an aralkyl group or an alkyl group such as diphenylmethyl, p-nitrobenzyl and t-butyl group. There is.

After the acylation reaction is complete, the deprotection reaction, ie the removal of the carboxyl protecting group, can be achieved by separation with known suitable methods, eg acids or reducing agents, depending on the nature of the protecting group used.

The carboxylate of general formula (III) used as the second starting material in the above method is known per se, but the cefem compound of general formula (II) is new because it has not been described in any literature.

The following briefly signs the general method for preparing compound (II), which has been studied and developed by the inventors, for the preparation of 2-methyl-7-amino-1-oxa-1-dethia-3-cefe-4-carboxylic acid. Some of the following examples described are illustrated, but are not limited to these. Compounds of formula (II) may be prepared by, for example, multi-step treatment starting from the following formula (IV) compounds.

In the above formula, Me is a methyl group, A 'is a carboxyl protecting group such as diphenylmethyl, and ph is a phenyl group.

Examples of compound (IV) include benzhydryl 3-methyl-2-[(1R, 5S) -3-phenyl-7-oxo-4- as described in Journal of chemical society, perkin I, P1932: 1975. Oxa-2,6-diazabicyclo [3,2,0] hepto-2-en-6-yl] or 2-2-inoate.

Compound (IV) is reacted with DL-α-hydroxyalkanoic acid alkyl ester of the following general formula (V) in the presence of trifluoromethanesulfonic acid at room temperature (step A).

In the above formula, R ₅ is the same as in formula (II), and B is an alkyl group such as ethyl group.

Thus, (3R, 4R) -4 {(1S) -1-alkoxycarboxyalkoxy} -3-benzamido-1- (1-protected carbonyl-2-methylprop-1- of formula (VI) Enyl) -azetidinone-2-one (-one) and (3R, 4R) -4-{(1R) -1-alkoxycarbonylalkoxy} -3-benzamido- of the following general formula (VI)- A diastereoisomer mixture consisting of 1- (1-protected carbonyl-2-methylprop-1-enyl) -igtidinone-2-one is obtained.

This mixture can be subjected to chromatography on silica gel using a developing solvent of benzyl-ethyl acetate (1: 1) to separate compounds of formula (VI) and (VII) from each other.

Compound (VII) is collected and reacted with methylene chloride at 0 ° C. in ozone gas (step B) to obtain an oxidized compound (unstable) of the following general formula (VIII).

As a reference, a similar reaction is shown in Japanese Patent Application No. 81-198466 invented by the inventors of the present application.

Compound (VIII) is reduced to zinc powder in acetic acid at low temperature (step C) to prepare an alcohol compound of the following formula (IX).

Compound (IX) is chlorinated with thionyl chloride in methylene chloride in the presence of pyridine (step D) to obtain a chloro compound with the following formula (X).

The chloro compound X was treated with triphenyl phosphine in chloroform at room temperature in the presence of a third amine such as kryalkylamine (step E) to replace the chlorine atom of compound (X) with a triphenylphosphoranylidene group. It produces a compound of food (XI).

The compound (XI) is hydrolyzed with an alkali such as sodium hydroxide in an acetone aqueous solution to remove the alkyl group (B) (step F). In this way, the corresponding carboxylic acid compound in which -OB is substituted with -OH in formula (XI) is obtained.

Before this reaction, the carboxylic acid compound (XI) can be subjected to the activity of the carboxyl group, for example, esterification.

For this purpose, the carboxylic acid compound (XI) is reacted with ethylchloroformate of the formula (XII) to cause ethoxycarbonylation (step G).

CI-COOEt (XII)

As a result, a compound having the formula

This compound (XIII) was reacted with diazomethane in ethyl ether at low temperature to obtain a diazo compound of the following formula (XIV).

The diazo compound is then reacted with hydrogen chloride in dioxane to replace the diazo group (step I) to obtain a chloro compound of formula (XV).

This chloro compound (XV) is reacted with a heterocyclic thiol compound of the following formula (XVI) (step J).

HS-Het (XVI)

In the above formula, -Het is a heterocyclic group.

This reaction is carried out with pyridine in methylene chloride to afford the compound of formula (XVII).

This compound (XVII) was subjected to cyclization by heating in toluene in the presence of hydroquinone (step K) to obtain 7α-benzamizo-2-alkyl-3- (heterocyclic) thioalkyl-1-oxa The compound of the following formula (XVIII) is produced as -1-dethia-3-cepem-4-carboxylic acid ester.

The alkyl group at 2-position of the compound (XVIII) takes on α-configuration.

On the other hand, when the compound of formula (VI) is used instead of compound (VII) in the above-described preparation method, the 2-alkyl group of compound (XVIII) takes the β-position.

In the 7-benzamino group of compound (XVIII), the benzoyl group (PhCO-) is reacted with phosphorus phenchloride in methylene chloride and treated with methanol as described in known methods such as Japanese Patent Publication No. 196-13862. Can be dislodged.

As a result, a compound of the following formula (XIX) is produced.

The same method as in JP-A-1975-50394 can be used to convert the steric configuration of the 7-amino group of the compound (XIX) from the α-form to the β-form.

This method reacts compound (XIX) with 3,5-di-t-butyl-4-hydroxybenzaldehyde to give its corresponding compound in the form of a Schiff base and then treats the oxidized compound obtained by treatment with an oxidant. Reduce to the required 7β-amino compound.

The same technique as in Japanese Patent Laid-Open No. 1970-50394 can be used to introduce the 7α-methoxy group to the 7-position of the compound (XIX).

Representative examples of the compound represented by the following general formula (II ′) are as follows.

In the above table, -CH ₂ -STz is a (1-methyl-1H tetrazol-5-yl) thiomethyl group and Me is a methyl group.

As described above, the 2-alkyl-7-amino-1-oxa-1-decia-3-cefem compound of general formula (II) is antimicrobial of general formula (I), and is a derivative of the new 7-N-acylated product. It is a new compound useful as an intermediate product in the synthesis production.

As described above, in order to further develop the present invention, the present inventors provide another member of the 2-alkyl-7-amino-1-oxa-1-dethia-3-cepem compound of general formula (II). In order to provide a new and efficient method for preparing a 7β-amino-2-alkyl-1-oxa-1-decia-3-cefem compound in which only 7-amino group takes its β-position, It was.

As a result of the study, the inventors have characterized the properties of the substituents at the 3-position of the cefe nucleus of the 2-alkyl-7-amino-1-oxa-1-decia-cefem compound of the general formula (II). It was successful to provide a method in which the substituent described with respect to the R ₆ group can be substituted with another substituent, and the beta-positioning of the steric configuration of the 7-amino group of the cephem nucleus is possible.

Accordingly, thirdly, the present invention provides a 4β-amino-2-alkyl-1-oxa-1-decia-cephalo-porin compound of the following general formula (IIa).

In the above formula, R ₄ is a hydrogen atom or a methoxy group, R ₅ is a lower alkyl group, R ₇ is a methyl group or halomethyl group or -CH ₂ -S-Het group (Het is a substituted or unsubstituted heterocyclic group), A Is a hydrogen atom or a carboxyl protecting group.

The new compounds of formula (IIa) are useful intermediate products when used in the synthesis of 7β-N-acylated-2-alkyl-1-oxa-1-dethia-cephalosporin derivatives which exhibit antimicrobial activity.

The 7β-amino-2-alkyl-1-oxa-1-dethia-cephalosporin compound of general formula (IIa) is a new compound that has not been described in any literature.

Representative examples of compound (IIa) according to the present invention include the following compounds.

(9) 7β-amino-7α-methoxy-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4- Carboxylic acid and its diphenylmethyl ester.

(10) 7β-amino-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylic acid and its Diphenylmethyl ester.

(11) 7β-amino-2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-dethia-3-cepem-4-carboxylic acid and its diphenyl Methyl ester.

(12) 7β-amino-7α-metholsi-2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4- Carboxylic acids and their diphenylmethyl esters.

(13) 7β-amino-2β, 3-dimethyl-1-oxa-1-dethia-3-cepem-4-carboxylic acid and diphenylmethyl esters thereof.

(14) 7β-amino-2α, 3-dimethyl-1-oxa-1-decia-3-cepem-4-carboxylic acid and diphenyl methyl esters thereof.

The compound of the general formula (IIa) according to the present invention is mainly treated to constitute a process step of cyclizing an azetidinone derivative obtained by condensing an oxazoli derivative with an α-hydroxyalkanoic acid alkyl ester as described above. It can manufacture by a method.

The treatment method for preparing compound (IIa) starting from an azetidinone derivative of formula (XVII ′) described below is schematically shown by the following reaction flowchart.

Therefore, fourthly, the present invention cyclizes azetidinone of the following general formula (XVII ') to produce a cefem compound of the following general formula (XVIII'), and the known method of the compound (XVIII ') Removing the R ₈ CO- group from the 7α-amino group to form a compound of the general formula (XIX ′); The compound (XIX ') is reacted with an aromatic aldehyde to produce a compound in the form of a Schiff base compound of the following general formula (XX); By carrying out steric translocation reaction of the Schiffbase-modified 7α-amino group of the compound (XX) or by beta-methoxylation at the 7-position of the compound (XX), a compound of the following general formula (XXIII) is produced. Decomposing the Schiff base component R ₉ -CHz in the compound (XXIII) by a conventional method; Preparation of 7β-amino-2-alkyl-1-oxa-1-dethia-cephalosporin compound of the general formula (IIa) characterized by leaving the carboxyl protecting group (A ') from the product compound obtained if necessary Provide a method.

Wherein R ₄ is a hydrogen atom or a methoxy group, R ₅ is a lower alkyl group, R ₇ is a methyl group or a -CH ₂ -S-Het group (Het is a substituted or unsubstituted heterocyclic group), A is a hydrogen atom or a carbon It is a compound saver.

The R ₈ CO- group is an acyl group, Ph is a phenyl group, A 'is a carboxyl protecting group, and R ₉ is an aromatic group as an example of a substituted aryl group, in particular a phenyl group or a 4-hydroxyphenyl group.

Starting compounds (IIa), intermediate compounds (SVIII ') to (XXIII) used in the preparation of compounds (XVII') and (I) of the present invention, R ₄ , R ₅ , R ₇ , R ₈ and A ' The following specific group is shown.

Acyl groups as R ₈ CO- groups are generally aromatic acyl groups.

Thus, the R ₈ group is an aromatic group, for example an aryl group, in particular a phenyl group or a substituted phenyl group, an arylalkyl group, an aryloxyalkyl group, an aralkyloxy group or a triphenylalkyl group.

By way of example, the R ₈ CO- group is preferably a phenylcarbonyl, phenylacetyl, benzyloxycarbonyl, phenoxymethylcarbonyl or tritylcarbonyl group.

The lower alkyl group of R ₅ is an alkyl group of C ₁ -C ₄ and may have a steric configuration of α or β.

In the α-stereoset or β-stereoset, R ₅ is preferably a methyl group.

The halomethyl group of R ₅ includes a methyl group substituted with one chlorine atom or one bromine atom.

Heterocyclic group in the heterocyclic thiomethyl group -CH ₂ -S-Het of R ₇ Het has a 5-membered heterocyclic group containing a hetero atom such as nitrogen, oxygen or sulfur atoms, and tetrazolyl, triazolyl and Thiazolyl groups are preferred.

Substituents present in the heterocyclic group are lower alkyl groups of C ₁ -C ₄ , in particular methyl and carboxy-lower alkyl groups, and are any of the substituents conventionally used as 3-substituents of known cephaltosporin.

R ₉ of the Schiff base residue group R ₉ -CH = group In general, an aromatic group, especially an aryl group, preferably a 4-hydroxy group.

These aromatic groups may also be substituted with lower alkyl such as methyl, isopropyl or t-butyl as examples.

The substitution position by the lower alkyl group is preferably 3,5-di-substituted.

A 'is any carboxyl protecting group.

These carboxyl protecting groups include conventional protecting groups used for known cephalosporins and penicillins. As an example, A 'is a substituted or unsubstituted aralkyl group such as diphenylmethyl, benzyl and P-nitrobenzyl, or a substituted unsubstituted alkyl group such as t-butyl and trichloroethyl.

The manufacturing method of the compound of general formula (IIa) by this invention (fourth) is demonstrated concretely according to the flowchart of the manufacturing method shown above.

First, a cyclization reaction in which compound (XVII ') is converted into compound (XVIII') is carried out, and a method of heating the compound (XVIII ') dissolved in an inert solvent, that is, in a witting reaction, To cyclize compound (XVIII ′) to achieve this reaction.

This reaction is carried out at a temperature of 40-120 ° C., preferably 100-120 ° C.

Inert solvents used in this reaction include ethers such as THF, dioxane, benzene, toluene, xylene and dimethoxyethane.

This reaction is preferably carried out under nitrogen or argon atmosphere in order to prevent the occurrence of color reaction, and can be carried out in the presence of a catalyst of hydroquinone added as an antioxidant.

When the R ₅ group of the compound (XVII ′) is R-positioned, the R ₅ group of the compound takes α-positioning, and when the R ₅ group of the compound is S-positioning, the R ₅ group takes the β-positioning.

The two process steps for preparing compound (XIX ') from compound (XVII') and converting compound (XIX ') to Schiff-based compound (XX) are each carried out by conventional methods.

Therefore, the process step of converting compound (XVIII ') to compound (XIX') is carried out by a so-called iminohalide-iminoether method (see Japanese Patent Publication No. 196-13862), and in the production of Schiff bases The process step of converting compound (XIX ') to compound (XX) is treated by reacting compound (XIX') with an aromatic aldehyde by the method described in JP-A-1975-50394. This process step is carried out by condensation of compound (XIX ') with an aromatic aldehyde such as 3,5-di-t-butyl-4-benzaldehyde in an inert solvent such as benzene, methyl chloride or ethyl acetate, and dehydration. XX).

The dislocation reaction for preparing compound (XXI) in compound (XX) is carried out by treating and oxidizing a solution of compound (XX) dissolved in an inert solvent, oxidizing to remove the oxidant, and then immediately adding a reducing agent.

Thus, the dislocation of the cubic arrangement of the clavicle in the 7-position occurs to obtain compound (XXI).

As the inert solvent used in this reaction, chloroform or methylene chloride is preferable as a suitable solvent which has been used for the known reaction of the β-lactam compound.

Suitable examples of oxidants used are manganese dioxide, nickel peroxide, lead tetraacetate and dichlorodicyanobenzoquinone (DDQ).

Preferred examples of reducing agents include sodium cyanoborohydride (NaBH ₃ CN), sodium borohydride (NaBH ₄ ), tetraethylammonium borohydride (Et ₄ NBH ₄ ) and tri-t-butoxylithium aluminum hydride (Li (t-Buo) ₃ A1H).

These two reactions were processed at a temperature of -20 ° C to 5 ° C.

The process step for preparing compound (XXII) in compound (XX) was treated by reverse reaction and methoxylated at the 7-position.

For this purpose, the method of JP-A-1975-50394 can be used conventionally.

Compound (XXIII) thus prepared (including Compound (XX I) and (XX II)) is then reacted for the purpose of decomposing the Schiff base type compound to obtain the desired carboxyl protecting intermediate compound (11b). .

The reaction for decomposing the Schiff base (XXIII) is carried out by a known method, for example, by the hydrolysis method of JP-A-1975-50394.

If necessary, the carboxyl protecting group (A ') is then removed from compound (11b) in a conventional manner to obtain compound (11a) (A is a hydrogen atom).

The new intermediate compound (11a) according to the present invention (third) has a high antibacterial activity of 7β-acyl-2-alkyl-1-oxa-1-de by a production method in which acylated 7-amino group leaves the carboxyl protecting group. It is useful as an intermediate because it can be converted immediately to thia-cephalosporin compounds.

The method for preparing the antimicrobial active compound from the general formula (IIa) compound has been described above in detail in the present invention (second).

Compound (XVII ') used as the first compound in the fourth production method of the present invention is a new compound that has not been described in any literature, and therefore, the production method developed by the present inventors will be described again below.

Compounds of formula (XVII ') can be prepared in multiple stages starting with the following formula (IV) compounds.

In formula, Me is a methyl group, A 'is a carboxyl protecting group, Ph is a phenyl group.

Compound (IV) is reacted with DL-α-hydroalkanoic acid alkyl ester of the following formula (V) in the presence of trifluoromethylsulfonic acid at room temperature.

In the formula, R ₅ is an alkyl group as R ₅ in the general formula (I), B is an alkyl group and the like.

As previously described, accordingly, (3R, 4R) -4 {(1S) -1-alkoxycarbonylalkoxy} -3-benzamido-1- (1-protected carbonyl-2- of the structure of formula (VI) Methylprop-1-enyl) -azetidin-2-one and (3R, 4R) -4 {(1R) -1-alkoxycarbonylalkoxy} -3-benzamido-1- of formula (VII) A diastereoisomer mixture consisting of (1-protected carbonyl-2-methylprop-1-enyl) -azetidin-2-one is obtained.

In the above formula, ph, A ', R ₅ and B are as described above.

The mixture can be chromatographed on silica gel using a developing solvent of benzene-ethyl acetate (7: 1) and the compounds of formula (VI) and (VII) can be separated from each other.

Formula (VI) in the conformational form required when substituting DL-form compound (V) for reaction with compound (IV) with its corresponding D-form R-form or L-form (S-form) compound Or (VII) can be obtained without subsequent chromatographic separation, respectively (see Reference Example 6).

Process steps may be carried out which pretreat the side chain groups at the 1- and 4-positions of the azetidinone compound (VI) or (VII) to produce the cefe ring required by compound (VI) or (VII).

The pretreatment step of the side chain group at the 1-position of compound (VI) or (VII) can be carried out by the process described above (see Reference Example 1).

The compound of formula (VII) is taken and reacted with ozone gas in methylene chloride at 0 ° C. to oxidize to yield the oxidation product (unstable) of the following formula (VIII).

Then, hydrolysis of the alcohol compound (IX), the chloro derivative (X), the phosphoranylidenated compound (X1), and the compound (XI) was continued until the next compound of the general formula (XVII) was obtained. Compound (VIII) obtained above was further treated according to the same process described above to obtain carboxylic acid compound, ethoxycarbonylate compound (XIII), diazo compound (XIV), and chloro compound (XV).

The same method as above the general formula the intermediate compound represented by the general formula (VI) takes the processing method is R ₅ S- disposed, bar, but that the embodiment described in (VII) R ₅ is R- compound takes place, as described previously Can be applied.

The product obtained by this treatment method is then cyclized to form a septum.

Alkyl groups in the 2-position of the formed septum ring are formed in the α-batch for the former but β-batch for the latter.

Treatments for compounds (VI) and (VII) are first carried out on the side chains in the 1-position and then on the side chains in the 4-position.

In either case, each reaction is treated under the same conditions as in the former case.

Reference Example 4 to be described below describes a process of first processing a side chain group in a 4-position.

The compound of formula (11a), wherein R _{7 according} to the third or fourth invention of the present invention is a halomethyl group, may be prepared, for example, when the chloro compound of formula (XV) is treated by the cyclization method of compound (XVII) described above. It may be.

Compounds obtained by the general formula (XVIII ′) wherein R ₇ is a halomethyl group are unstable and it is rather preferred to first convert compound (XV) to compound (XVII) and then cyclize the latter compound as described above.

Reference Example 5 first describes a method of preparing a starting compound containing a methyl group as R ₇ , that is, a general formula (XVIII ′) compound in which R _w is this methyl group, when carrying out a treatment method in which a 4-position conversion occurs. .

The treatment method of Reference Example 5 is characterized by the reduction production of the general formula (XVIII ′) compound in which R ₇ is a halomethyl group.

The halogen of the halomethyl group to be reduced is most preferably iodine.

The reduction reaction of the halomethyl group can be carried out under the same reduction state as in the case of pretreatment of the side chain group in the 1-position or the pretreatment of the side chain group in the 4-position.

In addition, the present invention is not limited to the following examples of the production method of the present invention and reference examples for the preparation of starting materials used in the production method of the present invention. In the following examples, Examples 1 to 8 refer to the first and second methods of the present invention, Examples 9 to 16 refer to the third and fourth inventions of the present invention, and Reference Examples 1 to 6 refer to the manufacturing methods of the present invention. Each of the processes for producing various starting materials used in the process will be described.

Example 1

(1) Diphenylmethyl 7- (2-thienylacetamido) -2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1- Preparation of Dethia-3-cepem-4-carboxylate

In the above formula, Me is a methyl group, Tz-Me is 1-methyl-1H-tetrazol-5-yl, and Ph is a phenyl group. 128 mg of diphenylmethyl7-amino-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylate To 4 ml of methylene chloride contained, 0.5 mg of methylene chloride containing 27 mg of pyridine and then 50 mg of 2-thienyl acetate chloride was added under ice-cooling, and the resulting mixture was stirred under ice-cooling at the same temperature for 30 minutes.

The obtained reaction solution was poured into 5 ml of ice water.

The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and then with water and dried over MgSO ₄ .

And evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel developed with a developing solvent of benzene-ethyl acetate (5: 1) to give the compound of Example (1), diphenylmethyl 7- (2-thienylacetamido). 125 mg (78%) of) -2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylate was obtained. .

(2) 7- (2-thienylacetamido) -2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia- Preparation of 3-cepem-4-carboxylic acid

100 mg of the product obtained in the process of Example (1) was added to an ice-cold mixture of 0.1 ml of anisole and 1 ml of trifluoroacetic acid and stirred at the same temperature for 30 minutes to remove diphenylmethyl group (deprotection).

The reaction solution thus obtained was evaporated, and the residue was triturated with isopropyl ether to obtain 68 mg (93%) of the compound of Example (2).

IR (Nujol), ν _max (cm ⁻¹ ): 1785, 1720, NMR (acetone-d ₅ ),

δ _ppm : 1.58 (3H, d, J = 6.8 Hz, 2-CH ₃ ), 3.88 (2H, s, -CH ₂ CO-), 3.99 (3H, S, tetrazol1-CH ₃ ), 4.17 and 4.55 (Each 1H, ABq, J = 13.6 Hz, -CH ₂ S-), 4.97 (1H, q, J = 6.8 Hz, 2-H), 5.38 (1H, d, J = 4 Hz, 6-H), 5.68 (1H, dd, J = 10, 4 Hz, 7-H), 6.80-7.35 (3H, m, thiophene).

Example 2

(1) Diphenylnetyl 7- (2-thienylacetamido) -2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1 Preparation of -Dethia-3-cepem-4-carbolsilite

81 mg of diphenylmethyl 7-amino-2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylate To 3 ml of methylene chloride, 0.5 ml of methylene chloride containing 17 mg of pyridine and then 31 mg of 2-thienyl acetic acid chloride was added under ice-cooling, the resulting mixture was stirred at the same temperature for 30 minutes, and the resulting reaction solution was poured into 5 ml of ice water. It was.

The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and then again with water.

And dried over MgSO ₄ , and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel suspended in a developing solvent of benzene-ethyl acetate (5: 1) to give 82 mg (81%) of the compound of the present example (1).

(2) 7- (2-thienylacetamido) -2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-decia-3-cepem Preparation of 4-carboxylic Acid

97 mg of the product obtained in Example 2 was subjected to deprotection to remove the diphenylmethyl group, and then treated as in Example 1- (2) to obtain 64 mg (91%) of the compound of this Example (2).

IR (Nujol), ν _max (cm ⁻¹ ): 1785, 1720, NMR (acetone-d ₅ ),

δ _ppm : 1.48 (3H, d, J = 6.8 Hz, 2-CH ₃ ), 3.85 (2H, s, -CH ₂ CO-), 3.98 (3H, s, tetrazol1-CH ₃ ), 4.10 and 4.87 (Each 1H, ABq, J = 13.0 Hz, -CH ₂ S-), 4.84 (1H, q, J = 6.8 Hz, 2-H), 5.15 (1H, d, J = 4.0, 6-H), 5.63 (1H, dd, J = 9.3,3.9 Hz, 7-H), 6.85-7.75 (3H, m, thiophene).

Example 3

(1) Diphenylmethyl 7β- (2-thienylacetamido) -7α-methoxy-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl- of the following formula Preparation of 1-oxa-1-dethia-3-cepem-4-carboxylate

Diphenylmethyl 7β-amino-7α-methoxy-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4- 6 ml of methylene chloride containing 100 mg of carboxylate was added to 18 ml of pyridine and 0.5 ml of methylene chloride containing 36 mg of 2-thienyl acetate chloride under ice-cooling, and the resulting mixture was stirred for 30 minutes at its glacier temperature.

The resulting reaction solution was poured into 5 ml of ice water, and the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, and then washed with water.

And dried over MgSO ₄ and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel developed with a benzene-ethyl acetate (5: 1) solvent to obtain 101 mg (82%) of the compound of [Example (1)].

(2) 7β- (2-thienylacetamido) -7α-methoxy-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dec Preparation of Thia-3-Cefe-4-carboxylic Acid

120 mg of the product obtained in the step of [Example 2- (1)] was added to an ice-cold mixture of 0.2 ml of anisole and 2 ml of trifluoroacetic acid, followed by stirring at the ice-cooling temperature for 30 minutes for deprotection.

The reaction solution thus obtained was evaporated, and the remaining oil was triturated with isoprefill ether to obtain 76 mg (85%) of the present compound [Example 3- (2)].

IR (Nujol), ν _max (cm ⁻¹ ): 1780, 1710 NMR (acetone-d ₅ ),

δ _ppm : 1.57 (3H, d, J = 6.7 Hz, 2-H), 3.44 (3H, s, -OCH ₃ ), 3.85 (2H, s, -CH ₂ CO-), 3.97 (3H, s, tetra Sol1-CH ₃ ), 4.16 and 4.50 (each 1H, ABq, J = 14 Hz, -CH ₂ S-), 4.18 (1H, q, J = 6.7 Hz, 2-H), 5.20 (1H, s, 6 -H), 6.80-7.35 (3H, m, thiophene).

Example 4

(1) diphenylmethyl 7β- (2-thienylacetamido) -7α-methoxy-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa- Preparation of 1-dethia-3-cepem-4-carboxylate

Diphenylmethyl 7β-amino-7α-methoxy-2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4- To 3 ml of methylene chloride containing 65 mg of carboxylate, 12 ml of pyritin and then 0.5 ml of methylene chloride containing 22 mg of 2-thienyl acetic acid chloride were added under ice-cooling, and the resulting mixture was stirred at that ice-cooling temperature for 20 minutes.

The obtained reaction solution was poured into 5 ml of ice water, and the organic layer was separated, washed with aqueous sodium carbonate solution under load, and then washed with water.

And dried over MgSO ₄ and evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel developed with benzene-ethyl acetate (3: 1 solvent) to give 70 mg (87%) of the present compound [Example 4- (1)].

(2) 7β- (2-thienylacetamido) -7α-methoxy-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dec Preparation of Thia-3-Cefe-4-carboxylic Acid

[0104] The obtained product in the above [Example 4- (1)] process was subjected to deprotection reaction and post-treatment in the same manner as in [Example 3- (2)] to 75 mg of the compound [Example 4- (2)]. (87%) was obtained.

IR (Nujol), ν _max (cm ⁻¹ ): 1782, 1712, NMR (acetone-d ₆ ),

δ _ppm : 1.38 (3H, d, J = 6.7 Hz, 2-CH ₃ ), 3.46 (3H, s, -OCH ₃ ), 3.87 (2H, s, -CH ₂ CO-), 3.98 (3H, s, Tetrazol1-CH ₃ ), 4.07 and 4.84 (1H, ABq, J Hz, -CH ₂ S-), 4.84 (1H, q, J = 6.8 Hz, 2-H), 5.00 (1H, s, 6 -H), 6.85-7.40 (3H, m, thiophene).

Example 5

(1) Diphenylmethyl 7β- [2- (2-thienyl) -2-diphenylmethoxycarbonyl acetamido] -7α-methoxy-2α-methyl-3- (1-methyl- Preparation of 1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylate

67 mg mono-diphenylmethyl 2-thienylmalonate and diphenylmethyl 7β-amino-7α-methoxy-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1- The solution obtained by dissolving 100 mg of oxa-1-dethia-3-cepem-4-carboxylate in 4 ml of methylene chloride was cooled to -30 ° C, and then mixed with 61 ml of pyridine and 19 ml of phosphorus oxychloride. The obtained mixture was stirred at a temperature of -30 ° C to 10 ° C for 30 minutes, and then at a temperature of -10 ° C to 0 ° C for 30 minutes.

The resulting reaction solution was poured into 5 ml of ice water, and the organic layer was separated, washed with an aqueous sodium bicarbonate solution, washed with water, and dried over MgSO ₄ .

The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography on silica gel using a developing solvent of benzene-ethyl acetate (5: 1) to give 117 mg (71) of the compound (Example 5- (1)). %) Was obtained.

(2) 7β- [2- (2-thienyl) -2-carboxacetamido] -7α-methoxy-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl Preparation of -1-oxa-1-dethia-3-cepem-4-carboxylic acid

117 mg of the product obtained in Example 5 (1) were subjected to deprotection reaction and post-treatment using the same treatment method as in Example 3- (2) to obtain 59 mg (83%) of the present compound (Example 5 (2)). .

IR (Nujol), ν _max (cm ⁻¹ ): 1782, 1722, NMR (acetone-d ₆ ),

δ _ppm : 1.53 (3H, d, 2-CH ₃ ), 3.42, 3.50 (3H, s, -OCH ₂ ), 3.96, 3.98 (3H, s, tetrazol1-CH), 4.17 and 4.51 (1H, respectively) ABq, -CH ₂ S-), 4.80 (1H, q, 2-H), 5.16 (1H, s, 6-H), 5.23 (1H, s, -CH-CO-), 6.80-7.40 (3H, m, thiophene).

Example 6

(1) diphenylmethyl7β- [2- (2-thienyl) -2-diphenylmethoxycarbonylacetamido] -7α-methoxy-2β-methyl-3- (1-methyl-1H-tetra Preparation of zol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylate

40 mg mono-diphenylmethyl 2-thienylmalonate and diphenylmethyl 7β-amino-7α-methoxy-2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1- The solution obtained by dissolving 100 mg of oxa-1-dethia-3-cefe-4-carboxylate in 3 ml of methylene chloride was cooled at a temperature of -30 ° C, and then mixed with pyridine 37 mu 1 and phosphorus oxychloride 19 mu 1. The mixture was stirred at a temperature of -30 ° C to 10 ° C for 30 minutes, and then at -10 ° C to 0 ° C for 30 minutes.

The resulting reaction solution was poured into 5 ml of ice water, the organic layer was separated, washed with saturated sodium bicarbonate solution, and then washed with water and dried over MgSO ₄ .

The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography on silica gel using a developing solvent of benzene-ethyl acetate (4: 1) to give 80 mg (82%) of the present compound (Example 6 (1)). Got it.

(2) 7β- [2- (2-thienyl) -2-carboxacetamido] -7β-methoxy-2β-methyl-3- (1-ketyl-1H-tetrazol-5-yl) thiomethyl Preparation of -1-oxa-1-dethia-3-cepem-4-carboxylic acid

160 mg of the product obtained in Example 6 (1) was subjected to deprotection reaction and post-treatment in the same manner as in Example 3- (2) to obtain 79 mg (81%) of the present compound.

IR (Nujol), ν _max (cm ⁻¹ ): 1780,1715, NMR (acetone-d ₆ ),

δ _ppm : 1.28, 1.39 (3H, d, 2-CH ₃ ), 3.41, 3.49 (3H, s, -OCH ₃ ), 3.89, 3.99 (3H, s, tetrazol1-CH ₃ ), 4.07, 4.82 ( 2H, ABq, -CH ₂ S-), 4.83 (1H, q, 2-H), 5.02 (1H, s, 6-H), 5.14, 5.16 (1H, s, -CH-CO-), 6.80- 7.40 (3H, m, thiophene).

Example 7

(1) Diphenylmethyl 7β- [2- (3-thienyl) -2-diphenylmethoxycarbonylacetamido] -7α-methoxy-2β-methyl-3- (1-methyl-1H-tetra Preparation of zol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylate

72 mg mono-diphenylmethyl 3-thienylmalonate and diphenylmethyl 7β-amino-7α-methoxy-2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1- The solution obtained by dissolving 90 mg of oxa-1-dethia-3-cepem-4-carboxylate in 4 ml of methylene chloride was cooled to -30 ° C and then mixed with pyridine 55μ 1 and phosphorus oxychloride 22μ 1.

The mixture was stirred at a temperature of -30 ° C to 10 ° C for 30 minutes and then at a temperature of -10 ° C to 0 ° C for 30 minutes.

The resulting reaction solution was poured into 5 ml of ice water, and the organic layer was separated, washed with saturated sodium bicarbonate solution, washed with water, and dried over MgSO ₄ .

The solvent was removed by evaporation under reduced pressure, and the residue was purified by column chromatography on silica gel using a developing solvent of benzene-ethyl acetate (5: 1) to give 120 mg (82%) of the present compound.

(2) 7β- [2- (3-thienyl) -2-carboxacetamido] -7α-methoxy-2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl Preparation of -1-oxa-1-oxa-1-dethia-3-cepem-4-carboxylic acid

147 mg of the product obtained in Example 7 (1) were deprotected and worked up in the same manner as in Example 3- (2) to give 74 mg (83%) of the present compound.

IR (Nujol), ν _max (cm ⁻¹ ): 1780, 1722, NMR (acetone-d ₆ ),

δ _ppm : 1.32, 1.38 (3H, d, 2-CH ₃ ), 3.39, 3.46 (3H, s, -OCH ₃ ), 3.98, (3H, s, tetrazole 1-CH ₃ ), 4.06, 4.80 (2H , ABq, -CH ₂ S-), 4.83 (1H, q, 2-H), 4.92, 4.95 (1H, s, 6-H), 5.00, 5.02 (1H, s, -CHCO-), 7.15-7.50 (3H, m, thiophene).

Example 8

(1) Diphenylmethyl 7- [2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -2α-methyl-3- (1-methyl- Preparation of 1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylate (syn-isomer)

In the above formula, Tr is a trityl group.

100 mg of diphenylmethyl 7-amino-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-tethia-3-cepem-4-carboxylate After dissolving 99 mg of 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid (syn-isomer) in 3 ml of methylene chloride, the resulting solution was cooled to -30 ° C, and pyridine 65μ was added to the solution. 1 and phosphorisoxychloride 26μ 1 were added. The mixture was stirred at a temperature of -30 ° C to 0 ° C for 30 minutes, and the reaction solution was poured into 5 ml of ice water. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, washed with water, dried and the solvent was evaporated.

The residue was purified by column chromatography on silica gel to give 156 mg (84%) of this compound in the form of a syn-isomer.

(2) 7- [2- (2-aminothiazol-4-yl) -2-methoxyimino-acetamido] -2α-methyl-3- (1-methyl-1H-tetrazol-5-yl ) Preparation of thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylic acid trifluoroacetate (syn-isomer).

156 mg of the product obtained in the above Example 8 (1) process was added to a mixture of 2 ml of trifluoro acetic acid and 0.2 ml of anisole under ice cooling and stirred for 30 minutes. A precipitate obtained by mixing 7 ml of isopropyl ether with the obtained reaction solution was filtered to obtain 61 mg (72%) of the present compound in the form of a syn-isomer.

NMR (DMSO-d ₆ ), δ _ppm : 1.58 (3H, d, J = 6.0Hz, 2-CH ₃ ), 3.99 (3H, s, tetrazole 1-CH ₃ ), 3.85 (3H, s, -OCH ₃ ), 4.16 and 4.54 (each 1H, ABq, J = 13.4 Hz, -CH ₂ S-), 4.96 (1H, q, J = 6.8 Hz, 2-H), 5.36 (1H, d, J = 4 Hz, 6 -H), 5.66 (1H, dd, J = 9, 4 Hz, 7-H), 6.75 (1H, s, thiazole, 5-H).

Example 9

(1) Diphenylmethyl 7α-benzamido-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4- Preparation of Carboxylate

(3R, 4R) -4-{(1R) -3- (1-methyl-1H-tetrazol-5-yl) thio-2-oxo-1-methylpropoxy} -3-benzami Fig. 1- (1-Diphenylmethoxycarbonyl-1-triphenyl-phosphoanilidenemethyl) azetidin-2-one was dissolved in 75 ml of toluene and 50 mg of hydroquinone was then added to this solution.

The mixture was heated at reflux for 9 hours to cause cyclization.

The resulting reaction solution was concentrated, and the residue was purified by column chromatography on silica gel developed with benzene-ethyl acetate (3: 1) to give 1.17 g (86%) of the present compound having the following structural formula. .

IR (CHCl ₃ ), ν _max (cm ⁻¹ ): 1787, 1718, 1672, 1600.

NMR (CDCl ₃ ), δ _ppm : 1.51 (3H, d, J = 6.9 Hz, 2-CH ₃ ), 3.81 (3H, s, tetrazol 1-CH ₃ ), 4.17, 4.40 (2H, ABq, J = 13 Hz, -CH ₂ S-), 4.80 (1H, q, J = 6.9 Hz, 2-H), 4.81 (1H, dd, J = 7.5, 1.0 Hz, 7-H), 5.28 (1H, d, J = 1.0 Hz, 6-H), 6.94 (1H, s, -CHph ₂ ), 7.10-8.70 (15H, m, C ₆ H ₅ x ₃ ).

(2) Diphenylmethyl 7α-amino-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxyl Manufacture of Rate

Pyridine (0.48 ml) was added to a solution obtained by dissolving 840 mg of PCl _{5 in} 24 ml of methylene chloride at 0 ° C, and the mixture was stirred at that temperature for 30 minutes.

To this reaction solution, 12 ml of methylene chloride containing 1200 ml of the product of Example 9 (1) was added dropwise at 0 ° C.

The mixture was stirred at 0 ° C. for 30 minutes, and stirred at 0 ° C. to 25 ° C. for 1 hour and cooled to 0 ° C. Then, the mixture obtained by adding 30 ml of methanol was stirred for another 10 minutes, and then stirred for 40 minutes at 0-25 ° C. to release the benzoyl group (phCO-).

The resulting reaction solution was poured into 600 ml of ice water, stirred for 30 minutes and concentrated. The residue was dissolved in 30 ml of ethyl acetate, washed with saturated aqueous sodium bitonate solution, washed with water, dried over MgSO ₄ and concentrated.

The residue was purified by column chromatography on silica gel using a developing solvent of benzene-ethyl acetate (1: 1) to give 630 ml (65%) of the present compound of the following structure.

IR (CHCl ₃ ), _msx (cm-1): 1779, 1713, 1620.

(3) diphenylmethyl 7α- (3.5-di-t-butyl-4-hydroxybenzylideneamino) -2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1 Preparation of -oxa-1-dethia-3-cepem-4-carboxylate

Example 9 (2) 600 mg of the product obtained in the step and 312 mg of 3,5-di-t-butyl-4-hydroxybenzaldehyde were dissolved in 60 ml of benzene in a Dean-stark apparatus for 45 minutes. Heated under reflux.

The resulting reaction solution was concentrated to give 910 mg of this Example compound of the following structural formula.

In formula, Me, t-Bu, ph, and -Tz-Me are methyl group, t-butyl group, a phenyl group, and the 1-methyl- 1H- tetrazol-5-yl group, respectively.

(4) diphenylmethyl 7β- (3,5-di-t-butyl-4-hydroxybenzylideneamino) -7α-methoxy-2α-methyl-3- (1-methyl-1H-tetrazol-5 Preparation of -yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylate

To the solution obtained by dissolving 910 mg of the product of Example 9 (3) in 15 ml of methylene chloride, 660 mg of MgSO ₄ and 600 mg of nickel peroxide were added under ice cooling. The resulting mixed fire was stirred at the ice cooling temperature for 10 minutes. The resultant product was oxidized to obtain a benzoquinone type intermediate having no stereochemical structure.

The reaction solution was then filtered and the filtrate was washed with 15 ml of methylene chloride.

And the liquid obtained by washing and filtrate were combined together. 30 ml of methanol was added to the filtrate under ice-cooling, and the resulting mixture was stirred at that temperature for 30 minutes to allow simultaneous reaction of introduction of 7-methoxy group and potential of benzylideneamino group.

The reaction solution thus obtained was concentrated to give 900 mg of this Example compound having the following structure.

(5) Diphenylmethyl 7β-amino-7α-methoxy-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-decia-3-cepem Preparation of 4-carboxylate

15 ml of methanol containing 400 mg of Girard T reagent was added to 900 mg of the product obtained in Example 9 (4) dissolved in 15 ml of ethyl acetate.

This mixed solution was stirred for 2 hours at room temperature to remove the substituted benzylidene group from the 7β-amino group.

The resulting reaction solution was concentrated, and the residue was dissolved in 200 ml of ethyl acetate.

This solution was washed with water, dried over MgSo ₄ and concentrated.

The residue was purified by column chromatography on silica gel with a developing solvent of benzyl-ethyl acetate (2: 1) to give 405 mg (64%) of the present compound of the following structure.

IR (CHCL ₃ ), ν _max (cm-1): 1782,1720,1603

NMR (CDCl ₃ ), δ ppm: 1.55 (3H, d, J6.8Hz, 2CH), 2.10 (2H, br.s, mino), 3.52 (3H, s, -OCH ₃ ), 3.79 (3H, s, tetra Sol 1-CH ₃ ), 4.15, 4.88 (2H, ABq, J = 14 Hz, -CH ₂ S-), 4.85 (1H, q, J = 6.8 Hz, 2-H), 4.97 (1H, s, 6- H), 6.90 (1H, s, -CHph ₂ ), 7.15 ~ 7.70 (10H, m, C ₆ H ₅ x2)

Example 10

(1) Diphenylmethyl 7β- (3,5-di-t-butyl-4-hydroxybenzylideneamino) -2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl Preparation of --1oxa-1-dethia-3-cepem-4-carboxylate

650 mg of the product obtained in Example 9 (2) was dissolved in 10 ml of methylene chloride, and 470 mg of MgSO _{4 and} 460 mg of nickel peroxide were dissolved in this solution under ice cooling.

The mixture was stirred at that temperature for 10 minutes to oxidize the product, yielding an intermediate in the form of benzoquinone without stereochemical structure.

The reaction solution was filtered, and the filtrate residue was washed with 10 ml of methylene chloride.

The washings and the filtrate were combined and ice-cooled, and 0.5 ml of methylene chloride including 38 mg of tetraethylammonium borohydride was added.

The mixture was stirred for 10 minutes at 2 temperature to generate a potential reaction to obtain a 7β- Schiff base compound.

The resulting reaction solution was poured into 20 ml of ice water. The reaction mixture was adjusted to pH 5.0 to separate the organic layer and washed with water.

And dried over MgSO ₄ and concentrated to give 630 mg of the present compound of the following structure.

(2) diphenylmethyl 7β-amino-2α-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-tethia-3-cepem-4-carboxyl Manufacture of Rate

To 630 mg of the product obtained in Example 10 (1) dissolved in 15 ml of ethyl acetate, 10 ml of methanol containing 290 mg of Girard reagent was added.

The mixture was stirred at room temperature for 1 hour to remove the substituted benzylidene group from the 7β-amino group.

The resulting reaction solution was concentrated, and the residue was dissolved in 20 ml of ethyl acetate.

The solution was washed with water, dried over MgSO ₄ and concentrated.

The residue was purified by column chromatography on a carousel with a developing solvent of benzene-ethyl acetate (1: 1) to give 151 mg (35%) of the present compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1785,1720,1602

NMR (CDCl ₃ ), δ _ppm : 1.57 (3H, d, J6.8Hz, 2CH), 2.06 (2H, br, s, mino), 3.82 (3H, s, tetrazol1-CH ₃ ), 4.21, 4.46 (2H, ABq, J = 14 Hz), 4.55 (1H, d, J = 4.5 Hz, 7-H), 4.86 (1H, q, J == 6.8 Hz, 2-H), 5.15 (1H, d, J = 4.5Hz, 6-H), 6.92 (1H, s, -CHph ₂ ), 7.15 ~ 7.70 (10H, m, C ₆ H ₅ x2)

Example 11

Diphenylmethyl7α-benzamido-2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-carboxylate Manufacturing,

(3R, 4R) -4-{(1S) -3- (1-methyl-1H-tetrazol-5-yl) thio-2-oxo-1-methylpropoxy} -3-benzamido of the structure 2.70 gr of -1- (1-diphenylmethoxycarbonyl-1-triphenylphospho-lanylidene-methyl) azetidin-2-one was dissolved in 270 ml of toluene and 180 mg of hydroquinone was added to the solution.

The mixture was heated under reflux for 20 minutes under nitrogen atmosphere, and the reaction solution was concentrated. The residue was purified by column chromatography on silica gel developed with benzene-ethyl acetate (4: 1) to give the present compound 1.50 g (81%) was obtained.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1780,1718,1668,1600

NMR (CDCl ₃ ), δ _ppm : 1.51 (3H, d, J6.8 Hz. 2 CH), 3.79 (3H, s, trazol 1-CH ₃ ), 4.03, 4.66 (2H, ABq, J = 14 Hz, -CH ₂ S-), 4.80 (1H, q, J = 6.8 Hz, 2-H), 4.89 (1H, dd, J = 7, 1 Hz, 7-H), 5.10 (1H, d, J = 1 Hz , (6-H), 6.85 (1H, d, J = 7 Hz, -CONH-), 6.92 (1H, s, -CHph ₂ ), 7.10-8.90 (15H, m, C ₆ H ₅ x3)

(2) Diphenylmethyl 7α-amido-2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-car Preparation of the carboxylates,

0.48 ml of paradine was added to 843 ml of PCl ₅ suspended in 24 ml of methylene chloride at 0 ° C., and the resulting mixture was stirred at that temperature for 30 minutes.

And 150 ml of methylene chlorides containing 1200 mg of the product obtained in Example 11 (1) were added dropwise to the solution thus obtained at 0 ° C.

The mixture was stirred at that temperature for 30 minutes, further baked at 0-25 ° C. for another hour and then cooled to 0 ° C. to which 12 ml of methanol were added.

The mixture was further stirred at that temperature for 10 minutes and further stirred at 0-25 ° C. for 40 minutes. The resulting reaction solution was poured into 50 ml of ice-water, and then plated for 30 minutes and concentrated.

The residue was dissolved in 30 ml of ethyl acetate, washed with saturated sodium bicarbonate solution, dried over MgSO ₄ , and concentrated.

The residue was purified by column chromatography on silica gel using a developing solvent of benzene-ethyl acetate (1: 1) to obtain 500 mg (50%) of the present compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1778,1723,1608

NMR (CDCl ₃ ), δ _ppm : 1.49 (3H, d, J6.8 H2,2CH), 2.00 (2H, br, s, mino), 3.77 (3H, s, tetrazol 1-CH ₃ ), 4.04, 4.63 (2H, ABq, J = 14 Hz, -CH ₂ S-), 4.05 (1H, d, J = 1 Hz, 7-H), 4.75 (1H, d, J = 1 Hz, 6-H), 4.80 ( 1H, q, J = 6.8 Hz, 2-H), 6.90 (1H, s, -CHph ₂ ), 7.10-7.70 (10H, m, C ₆ H ₅ x2)

(3) diphenylmethyl 7α- (3.5-di-t-butyl-4-hydroxybenzylideneamino) -2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1 Preparation of oxa-1-dethia-3-cepem-4-carboxylate,

The mixture obtained by dissolving 350 mg of the product obtained in Example 11 (2) and 184 mg of 3.5-di-t-butyl-4-hydroxybenzaldehyde in 100 ml of benzene was heated at reflux for 50 minutes in a Dean-Stark apparatus.

The resulting reaction solution was concentrated to give 530 mg of compound in this Example of the following structure.

NMR (CDCl ₃ ), δ _ppm : 1.47 (18H, s, t), 1.57 (3H, d, J = 6.8Hz, 2-CH ₃ ), 3.80 (3H, s, tetrazol 1-CH ₃ ), 4.08 (2H, ABq, J = 14 Hz, -CH ₂ S-), 4.71 (1H, br, s, 7-H), 4.82 (1H, q, J = 6.8, 2-H), 5.16 (1H, s, J = 1 Hz, 6-H), 5.56 (1H, s, -OH), 6.90 (1H, s, -CHph ₂ ), 7.10 to 7.75 (10H, m, C ₆ H ₅ x2) 7.60 (2H, s , C ₆ H ₅ ), 8.35 (1H, d, J = 1 Hz, -CH = N-)

(4) Diphenylmethyl 7β- (3.5-di-t-butyl-4-hydroxy benzylideneamino) -2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1 Preparation of oxa-1-dethia-3-cepem-4-carboxylate.

327 mg of the product of Example 11 (3) was dissolved in 5 ml of methylene chloride and 236 mg of MgSO _{4 and} 236 mg of nickel peroxide were added to the solution under ice cooling.

The mixture was stirred for 10 minutes at its ice-cold temperature, and then the reaction solution was filtered to wash the filter residue with 5 ml of methylene chloride.

The washed solution and the filtrate were combined together. The resulting solution was ice-cooled, and 0.1 ml of methylene chloride containing 16 mg of tetraethylammonium borohydride was added.

The resulting mixture was stirred for 10 minutes at its ice cooling temperature and added to 10 ml of ice water to generate a potential reaction at the 7-position.

The reaction mixture was then adjusted to ph5.0, the organic layer was separated, washed with water, dried over MgSO ₄ and concentrated.

As a result, 309 mg of this compound of the following structure was obtained.

(3) Diphenylmethyl-7β-amino-2β-methyl-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-dethia-3-cepem-4-car Preparation of Cyclate

The solution obtained by dissolving 309 mg of the product obtained in Example 11 (4) in 5 ml of ethyl acetate was added to 5 ml of methanol, which contained 145 mg of Girard T reagent, and the resulting mixture was stirred at room temperature for 1 hour.

Then, the resulting reaction solution was concentrated. The residue was dissolved in 20 ml of ethyl acetate, and the solution was washed with water, dried over MgSO ₄ and evaporated.

The residue was purified by column chromatography on a preparative gel with a developing solvent of benzene-ethyl acetate (1: 1) to give 66 mg (31%) of the present compound of the following structure.

m.p. 131-133 ° C (decomposition)

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1783, 1720, 1602

NMR (CDCl ₃ ), δ _ppm : 1.53 (3H, d, J6.8 Hz, 2CH), 2.12 (2H, br, s, mino), 3.70 (3H, s, tetrazole 1-CH ₃ ). 4.02, 4.07 (2H, ABq, J = 14 Hz, -CH ₂ S-), 4.45 (1H, d, J = 5 Hz, 7-H), 4.80 (1H, q, J = 6.8 Hz, 2H), 4.97 (1H, d, J = 5Hz, 6-H), 6.84 (1H, s, -CHph ₂ ), 7.10 ~ 7.65 (10H, m, C ₆ H ₅ x2)

Example 12

(1) Diphenylmethyl 7β- (3.5-di-t-butyl-4-hydroxy benzylideneamino) -7α-methoxy-2-methyl-3- (1-methyl-1H-detrazole-5- I) Preparation of thiomethyl-1-oxa-1-dethia-3-cef-4-carboxylate

530 mg of the product obtained in Example 11 (4) was dissolved in 8 ml of methylene chloride, and 380 mg of MgSO ₄ and 300 mg of kelp peroxide were added to the solution under ice-cooling.

The mixture was then baked at that temperature for 10 minutes, filtered, and the filtered residue was washed with 8 m of methylene chloride.

The wash and filtrate were combined together. Then 10 ml of methanone were added to the combined filtrates under ice cooling.

The resulting mixture was stirred at that temperature for 30 minutes to allow simultaneous reaction for the introduction and conduction of 7α-methoxy groups.

The resulting reaction solution was concentrated to give 490 mg of this Example compound having the following structure.

NMR (CDCl ₃ ), δ _ppm : 1.33 (3H, d, J6.8 Hz, 2CH), 1.47 (18H, s, tbutyl), 3.59 (3H, s, -OCH ₃ ), 3 80 (3H, s , Tetrazole 1-CH ₃ ), 4.07, 4.70 (2H, ABq, J = 14 Hz, -CH ₂ S-), 4.77 (1H, q, J = 6.8 Hz, 2-H), 5.08 (1H, s , 6-H), 5.59 (1H, s, -OH), 6.91 (1H, s, -CHph ₂ ), 7.10-7.80 (10H, m, C ₆ H ₅ x2), 6.66 (2H, s, CH ₅ ), 8.44 (1H, s, -CH = N-)

(2) Diphenylmethyl 7β-amino-7α-methoxy-2β-methyl-3 (1-methyl-1H-tetrazol-5-yl) thiomethyl-1-oxa-1-decia-3-cepem- Preparation of 4-carboxylate

490 mg of the product of Example 12 (1) was dissolved in 8 ml of ethyl acetate, and 8 ml of methanol containing 240 mg of Girard T reagent was added to this solution.

The mixture was stirred at rt for 1.5 h and then concentrated.

The residue was dissolved in 10 ml of ethyl acetate, the solution was washed with water, dried over MgSO ₄ and concentrated.

The residue was purified by column chromatography on silica gel with a developing solvent of benzyl-ethyl acetate (2: 1).

As a result, 241 mg (65%) of this Example compound of the following structure was obtained.

m. p. 133 ~ 135 ℃ (decomposition)

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1783, 1720, 1600

NMR (CDCl ₃ ), δ _ppm : 1.53 (3H, d, J6.8 Hz, 2CH), 2.12 (2H, br, s, mino), 3.70 (3H, s, tetrazol 1-CH ₃ ), 4.02, 4.07 (2H, ABq, J = 14 Hz, -CH ₂ S-), 4.45 (1H, d, J = 5 Hz, 7-H), 4.80 (1H.qJ = 6.8 Hz, 2H), 4.97 (1H, d, J = 5Hz, 6-H, 6.84 1H, s, -CHph ₂ ), 7.10 ~ 7.65 (10H, m, C ₆ H ₅ x2)

Example 13

(1) Diphenylmethyl 7α-benzamide-2α-methyl-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-1-oxa-1-dethia-3- Preparation of Cefem-4-carboxylate

(3R, 4R) -4-{(1R) -3 (2-methyl-1,3,4-thiadiazole-5-) thio-2-oxo-1-methylpropoxy} -3-benzamido 1.70 g of -1- (1-diphenylmethoxycarbonyl-1-triphenylphosphoranylidene-methyl) azetidin-2-one was dissolved in 30 ml of toluene, and then 100 mg of hydroquinone was added to this solution. The mixture was heated to reflux for 10 hours under nitrogen atmosphere. The resulting reaction solution was concentrated and the residue was purified by column chromatography on silica gel with a developing solvent of benzene-ethyl acetate (3: 1). As a result, 0.95 g (8.1%) of the present Example compound of the following structure was obtained.

IR (CHCl ₃ ), ν _max (cm ⁻¹ ): 1874, 1719, 1668, 1600

NMR (CDCl ₃ ), δ _ppm : 1.48 (3H, d, J = 6.8 Hz, 2-CH ₂ ), 2.68 (3H, s, thiadiazole 2-CH ₃ ), 4.31 (2H, br, s,- CH _2- ), 4.79 (1H, q, J = 6.8 Hz, 2-H), 4.90 (1H, dd, J = 8.91 Hz, 7-H), 5.24 (1H.dJ = 1 Hz, 6-H), 6.94 (1H, s, CHph ₂ ), 7.10 ~ 7.85 (15, m, C ₆ H ₅ x3)

Example 14

(1) Preparation of diphenylmethyl 7α-benzamide-2β, 3-dimethyl-oxa-1-dethia-3-cepem-4-carboxylate (3R, 4R) -4-{(1S) -2- Dissolve 100 mg of oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-phosphoranilidenemethyl) azetidin-2-one in 10 ml of dioxane The solution was heated to reflux for 52 hours under nitrogen atmosphere. The resulting reaction solution was concentrated. The residue was purified by column chromatography on silica gel to give 20 mg (31%) of the compound of this example in the following structure.

NMR (CDCl ₃ ), δ _ppm : 1.42 (3H, d, J = 6.8Hz, 2-CH ₃ ), 1.95 (3H, s, 3-CH ₃ ), 4.32 (1H, q, J = 6.8Hz, 2 -H), 4.94 (1H, dd, J = 7,1 Hz, 7-H), 4.97 (1H, d, J = 1 Hz, 6-H), 6.90 (1H.s.-CHph ₂ ), 7.00-7.80 (15HJ, m, C ₆ H ₅ x3)

(2) Preparation of diphenylmethyl 7α-amino-2β, 3-dimethyl-1-oxa-1-dethia-3-cepem-4-carboxylate

1.0 ml of pyridine was added to 1750 mg of PCl ₅ at 0 ° C. and the mixture was dissolved in 45 ml of methylene chloride and stirred at that temperature for 30 minutes.

15 ml of methylene chloride containing 2030 mg of the product obtained in Example 14 (1) was added dropwise to the solution thus obtained at 0 ° C.

The mixture was stirred at that temperature for 30 minutes and at 0-25 ° C. for 1 hour. The mixture was then cooled to 0 ° C. to add 25 ml of methanol. The mixture was further stirred for 1 hour at that temperature and for 2 hours at 0-25 ° C. The resulting reaction solution was poured into 50 ml of ice water and stirred for 30 minutes. And concentrated.

The residue was dissolved in 50 ml of ethyl acetate, washed with water, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography on silica gel using a developing solvent of benzene-ethyl acetate (2: 1) to give 960 mg (60%) of the present compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-21 ): 1770, 1718

NMR (CDCl ₃ ), δ _ppm : 1.37 (3H, d, J = 6.8Hz, 2-CH ₃ ), 1.84 (2H, s, 3-H ₂ N-), 1.91 (3H, d, J = 0.9Hz , 3-CH ₃ ), 4.01 (1H, s, 7-H), 4.35 (1H, q, J = 6.8 Hz, 2-H), 4.72 (1H.s.6-H), 6.92 (1H, s , -CHph ₂ ), 7.100 ~ 7.60 (10H, m, C ₆ H ₅ x2)

(3) diphenylmethyl 7α- (3.5-di-t-butyl-4-hydroxybenzylideneamino) -2β, 3-dimethyl-1-oxa-1-dethia-3-cepem-4-carboxylate Manufacture

Example 14 (2) 960 mg of the product obtained in the step and 654 mg of 3,5-di-t-butyl-4-hydroxybenzaldehyde were dissolved in 50 ml of benzene. This mixture was heated to reflux in a Dean-Stark apparatus for 1 hour.

As a result, the reaction solution was concentrated to give 1500 mg of the compound in this example having the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1770, 1719, 1680

NMR (CDCl ₃ ), δ _ppm : 1.41 (3H, d, J = 6.8 Hz, 2-CH ₃ ), 1.46 (18H, s, t-Bu), 1.97 (3H, d, J = 0.9Hz, 3- CH ₃ ), 4.44 (1H, q, J = 6.8 Hz, 2-H), 4.70 (1H, br, s, 7-H), 5.13 (1H.br.s, 6-H), 5.58 (1H, s, -CH), 6.90 (1H, s, CHph ₂ ), 7.10 ~ 7.70 (10H, m, C ₆ H ₅ x2), 7.64 (2H, s, C ₆ H ₂ ), 8.41 (1H, d, J = 1.5 Hz, -CH = N-).

(4) diphenylmethyl 7β- (3,5-di-t-butyl-4-hydroxybenzylideneamino) -2β, 3-dimethyl-1-oxa-1-dethia-3-cepem-4-car Preparation of Cyclate

1400 mg of the product of Example 14 (3) was dissolved in 30 ml of methylene chloride, and MgSO ₄ , 950 mg and nickel peroxide 950 mg were added to the solution under ice cooling.

The mixture was stirred for 10 minutes at its ice cooling temperature. The reaction solution was then filtered and the filtered residue was washed with 30 ml of methylene chloride. The wash and filtrate were combined together.

The combined filtrates were cooled to −20 ° C. and then 2 ml of methylene chloride containing 100 mg of tetraethylammonium borohydride was added.

The mixture thus obtained was stirred at that temperature for 10 minutes and then poured into 50 ml of ice water.

The reaction mixture was adjusted to ph 5.0, and the organic layer was separated, washed with water, dried over MgSO ₄ and concentrated. Then, 1200 mg of the compound of the example structure was obtained.

(5) Preparation of diphenylmethyl 7β-amino-2β, 3-dimethyl-1-oxa-1-dethia-3-cepem-4-carboxylate

In Example 14 (4), 1200 mg of the product was dissolved in 14 ml of ethyl acetate, and 14 ml of methanol, which contained 600 mg of Girard T reagent, was added.

The mixture was stirred for 1 hour at room temperature and then concentrated. The residue was dissolved in 45 ml of ethyl acetate, and the resulting solution was washed with water, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography on silica gel with a developing solvent of benzene-ethyl acetate (1: 1) to give 488 mg (64%) of the present compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ⁻¹ ): 1778, 1718

NMR (CDCl ₃ ), δ _ppm : 1.41 (3H, d, J = 6.8Hz, 2-CH ₃ ), 1.84 (2H, br, s, H ₂ N-), 1.98 (3H, d, J = 0.9Hz , 3-CH ₃ ), 4.40 (1H, q, J = 6.8 Hz, 2-H), 4.45 (1H, d, J = 4.0 Hz, 7-H), 4.98 (1H.qJ = 4.0 Hz, 6- H), 6.89 (1H, s, -CHph ₂ ), 7.10-7.60 (10H, m, C ₆ H ₅ x 2)

Example 15

(1) Preparation of diphenylmethyl 7α-benzamide-2α, 3-dimethyl-1-oxa-1-decia-3-cepem-4-carboxylate

(3R, 4R) -4 {(1R) -2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-phosphoranylidenemethyl) ase 1.30 g of thidin-2-one was dissolved in 120 ml of toluene and 70 ml of hydroquinone was added to the solution.

The mixture was heated to reflux for 40 hours under nitrogen atmosphere to concentrate the reaction solution.

The residue was purified by column chromatography on silica gel to obtain 0.43 g (52%) of an example compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1770, 1718, 1660

NMR (CDCl ₃ ), δ _ppm : 1.38 (3H, d, J = 6.9 Hz, 2-CH ₃ ), 2.02 (3H, s, 3-CH ₃ ), 4.42 (1H, q, J = 6.9 Hz, 2 -H), 4.99 (1H, dd, J = 7.6, 1 Hz, 7-H), 5.13 (1H, s, 6-H), 6.91 (1H.s, -CHph ₂ ), 7.00-9.90 (15H, m , C ₆ H ₅ x3)

(2) Preparation of diphenylmethyl 7α-amino-2α, 3-dimethyl-1-oxa-1-dethia-3-cef-4-carboxylate

1.0 ml of pyridine was added to 1720 mg of PCl ₅ at 0 ° C. and dissolved in 40 ml of methylene chloride. This mixed solution was stirred at that temperature for 30 minutes. 15 ml of methylene chloride containing 2000 mg of the product of the Example 15 (1) step was added dropwise to the solution thus obtained at 0 ° C.

The mixture was stirred for 30 minutes at that temperature and for another hour at 0-25 ° C.

The so treated mixture was then cooled at 0 ° C. and 25 ml of methanol.

The mixture was further stirred at that temperature for one hour and further at 0-25 ° C. for one hour.

The resulting reaction solution was poured into 40 ml of ice water, stirred for 30 minutes and concentrated.

The residue was dissolved in 50 ml of ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, washed with water, dried over MgSO ₄ , and concentrated.

The residue was purified by column chromatography on silica gel using a developing solvent of benzene-ethyl acetate (2: 1) to give 1035 mg (66%) of the compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1773, 1720

NMR (CDCl ₃ ), δ _ppm : 1.40 (3H, d, J = 6.9Hz, 2-CH ₃ ), 1.88 (2H, br, s, -NH ₂ ), 2.01 (3H, s, 3-CH ₃ ) , 4.02 (1H, br, s, 7-H), 4.37 (1H, q, J = 6.9 Hz, 2-H), 4.87 (1H, br, s, 6-H), (1H, s, -CHph ₂ ), 7.10-7.60 (10H, m, C ₆ H ₅ x 2).

(2) diphenylmethyl 7α- (3.5-di-t-butyl-4-hydroxybenzylideneamino) -2α, 3-dimethyl-1-oxa-1-dethia-3-cepem-4-carboxylate Manufacture

1000 mg of the product obtained in Example 15 (2) and 680 mg of 3,5-di-t-butyl-4-hydroxybenzaldehyde were dissolved in 50 ml of Benze, and the mixture was heated to reflux in a Dean-Stark apparatus for one hour.

The resulting reaction solution was concentrated to give 1571 mg of this Example compound.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1775, 1720, 1682

NMR (CDCl ₃ ), δ _ppm : 1.40 (3H, d, J = 6.9 Hz, 2-CH ₃ ), 1.46 (18H, s, t-Bu), 2.05 (3H, s, 3-CH ₃ ), 4.43 (1H, q, J = 6.9 Hz, 2-H), 4.68 (1H, br.s, 7-H), 5.27 (1H, s, 6-H), 5.57 (1H, s, -OH), 6.92 (1H, s, -CHph ₂ ), 7.10 ~ 7.70 (10H, m, C ₆ H ₅₎ ) x2), 7.60 (2H, s, -C ₆ H ₂ ), 8.41 (1H, d, 1.5Hz,- CH = N-).

(4) diphenylmethyl 7β- (3.5-di-t-butyl-4-hydroxybenzylideneamino) -2α, 3-dimethyl-1-oxa-1-dethia-3-cepem-4-carboxylate Manufacture

1500 mg of the product of Example 15 (3) was dissolved in 30 ml of methylene chloride, to which 970 mg of MgSO _{4 and} 970 mg of nickel peroxide were added under ice cooling.

And the mixture was stirred for 10 minutes at that temperature. The reaction solution was then filtered and the filtered residue was washed with 30 ml of methylene chloride. The washing and the filtrate were combined. The combined filtrates were then cooled to −20 ° C. and 2 ml of methylene chloride containing 110 mg of tetraethylammonium borohydride were added.

The mixture thus obtained was stirred at that temperature for 10 minutes and poured into 50 ml of ice water.

The reaction mixture was adjusted to ph 5.0, and the organic layer was separated, washed with water, dried over MgSO ₄ , and concentrated. As a result, 1400 mg of the present compound of the following structure was obtained.

(5) Preparation of diphenylmethyl 7β-amino, 2α, 3-dimethyl-1-oxa-1-dethia-3-cepem-4-carboxylate

Example 15 (4) 15 ml of methanol containing 690 mg of Girard T reagent was added to a solution of 1400 mg of the product dissolved in 15 ml of ethyl acetate.

The mixture was stirred for 1 hour at room temperature and then concentrated. The residue was dissolved in 50 ml of ethyl acetate, and the resulting solution was washed with water, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography on silica gel developed with benzene-ethyl acetate (1: 1) to give 587 mg (66%) of the present compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1782, 1719, 1600

NMR (CDCl ₃ ), δ ppm: 1.44 (3H, d, J = 6.9 Hz, 2-CH ₃ ), 1.86 (2H, br, s, -NH ₂ ), 2.06 (3H, s, 3-CH ₃ ), 4.44 (1H, q, J = 6.9 Hz, 2-H), 4.49 (1H, d, J = 3.8 Hz, 7-H), 5.13 (1H, d, J = 3.8 Hz, 6-H), 6.90 ( 1H, s, CHph ₂ ), 7.10-7.70 (10H, m, C ₆ H ₅ x 2).

Example 16

(1) Preparation of diphenylmethyl 7α-benzamide-2α-methyl-3-chloromethyl-1-oxa-1-dethia-3-cepem-4-carboxylate

(3R, 4R) -4-{(1R) -3-chloro-2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmetholoxycarbonyl-1) 1.59 g of -triphenylphosphoranylidenemethyl) azetidin-2-one was dissolved in 50 ml of toluene.

The solution was heated to reflux for 3 hours and then concentrated. The residue was purified by column chromatography on silica gel developed with benzene-ethyl acetate (5: 1), to obtain 0.70 g (68%) of the present compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1786, 1728, 1663, 1602

NMR (CDCl ₃ ), δ _ppm : 1.46 (3H, d, J = 6.9 Hz, 2-CH ₃ ), 4.22, 4.53 (2H, ABq, J = 11.5 Hz, -CH ₂ Cl), 4.78 (1H, q , J = 6.9 Hz, 2-H), 4.95 (1H, dd, J = 7.5,1 Hz, 7-H), 5.23 (1H, d, J = 1 Hz, 6-H), 6.95 (1H, s,- CHph ₂ ), 7.00-7.90 (15H, m, C ₆ H ₅ x 2).

(2) diphenylketyl7α-benzamido-2α-methyl-3- (1,3,4-thiadiazol-5-yl) thiomethyl-1-oxa-1-decia-3-cepem-4 Preparation of Carboxylate

Example 16 (1) 10 ml of an aqueous solution containing 220 mg of 5-mergato-1,3,4-thiadiazole, NaHCO ₃ , 260 mg and 70 mg of tetraethylammonium chloride in a solution of 800 mg of the product of the process in 20 ml of methylene chloride Was added.

The resulting mixture was stirred for 2 hours at room temperature, the organic layer was separated, washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel with a developing material of benzene-ethyl acetate (3: 1) to give 580 mg (63%) of this example compound in the following structure.

m.p. 170 to 172 ° C (decomposition)

IR (CHCL _3), ν _max (cm ⁻¹ ): 1782, 1718, 1665, 1600.

NMR (CDCl ₃ ), δ ppm: 1.52 (3H, d, J = 6.8 Hz, 2-CH ₃ ), 4.41 (2H, br, s, -CH ₂ S-), 4.82 (1H, q, J = 6.8 Hz , 2-H), 4.90 (1H, dd, J = 7,1 Hz, 7-H), 5.26 (1H, d, J = 1 Hz, 6-H), 6.96 (1H, s, -CHph ₂ ), 7.06 (1H, d, J = 7.1 Hz, -CONH-), 7.10 -7.90 (15H, m, C ₆ H ₅ x3), 8.96 (1H, s, thiadiazole 2H)

Reference Example 1

(1) (3R, 4R) -4-{(1) -1-ethoxycarbonylethoxy} -3- benzabel-1- (1-diphenylmethoxycarbonyl-2-methylprop-1- Enyl) -azididin-2-one (compound a) and (3R, 4R) -4-{(1R) -1-ethoxycarbonylethoxy} -3-benzamido-1- (1-diphenyl Preparation of Fethoxycarbonyl-2-methylprop-1-ethyl) azetidin-2-one (Compound b) (Step A)

(1R, 5R) -3-phenyl-6- (1-diphenylmethoxy-carbonyl-2-methylprop-1-enyl) -7-oxo-2, 6-diazabicyclo [3, 10 g of hepto-2-ene (see Chemical Society perkin I, P, 1932,1975) was dissolved in 35 ml of DL-α-ethyl acetate having the following structure.

In formula, ph is a phenyl group, Me is a methyl group, and Et is an ethyl group.

0.5 ml of trifluoromethanesulfonic acid was added to the solution thus treated.

The mixture was stirred at room temperature for 1.5 hours to ring-open, and the starting compound was condensed.

The reaction solution thus obtained was poured into 200 ml of aqueous sodium bicarbonate solution and allowed to stand for 30 minutes under ice cooling.

The aqueous layer was removed and the oily product was separated, dissolved in 70 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and then washed with water. And dried over MgSO ₄ and concentrated.

The residue containing the two diastereoisomers formed as a product was treated by column chromatography on silica gel developed with benzyl-ethyl acetate (7: 1) developing solvent to separate the two diastereoisomers required, respectively, and then ethyl ether. Crystallized with (3R, 4R) -4 {(1S) -1-ethoxycarbonylethoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-2-methylprop 2.1 g of -1-enyl) azetidin-2-one (compound a)

(3R, 4R) -4-{(1R) -1-1ethoxycarbonylethoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-2-methylprop) having the following structure 2.05 g of 1-enyl) azetidin-2-one (compound b) was obtained.

Properties of compound a

m.p. 104 ~ 1.6 ℃

[α} _D -75 ⁰ (C 1.0 in CHCl ₃ )

IR (CHCl ₃ ), ν _max (cm ⁻¹ ) 1763, 1738, 1661, 1602:

Properties of Compound B

m.p. 133 ~ 5 ℃

[α} _D -2.1 ⁰ (C 1.0 in CHCl ₃ )

IR (CHCL ₃ ), ν _max (cm ^-1 ) 1768, 1735, 1668, 1600:

(2) (3R, 4R) -4-{(1R) -1- ethoxycarbonylethoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-hydroxy-methyl Preparation of Azetidin-2-one (Step B + C Step)

5.0 g of compound b obtained in Reference Example (1) was dissolved in 150 ml of methylene chloride and passed through this solution at -60 ° C until ozone turned blue.

Thus, compound (b) was converted into the compound (c) of the following structure.

(See Reference Examples 1 (a) to (iv) described in Japanese Patent Application No. 81-198466, filed by the inventors.)

1 g of zinc powder and 1 ml of acetic acid were added to -60 ° C. to the reaction solution containing the compound (c), the temperature of the mixture was raised to 0 ° C., and 10 g of zinc powder and 10 ml of acetic acid were further added.

The resulting mixture was stirred for 30 minutes to generate a reduction reaction.

The reaction mixture thus obtained was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate solution and then with water.

And dried over MgSO ₄ and concentrated to give 4.3g (90%) of this reference example compound of the following structure.

(3) (3R, 4R) -4-{(1R) -1-ethoxycarbonylethoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-chloro-methyl) Preparation of Azetidin-2-one (Step D)

4.58 g of the product of Reference Example 1 (2) was dissolved in 50 ml of methylene chloride, and cooled. Then, 1.38 g of pyridine and 2.08 g of thionyl chloride were added to the solution, followed by stirring for 30 minutes, for a chlorination reaction.

The reaction solution was poured into ice water to separate the organic layer, washed with saturated aqueous sodium bicarbonate solution, and then washed with water. And dried over MgSO ₄ and concentrated.

Thus, 4.50 g (95%) of this Example compound of the following structure was obtained.

(4) (3R, 4R) -4-{(1R) -1-ethoxycarbonylethoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-triphenyl-force Preparation of Foranilidenemethyl) azetidin-2-one (Step E)

4.5 g of the product of Reference Example 1 (3) was dissolved in 50 ml of chloroform, and 1.46 ml of triethylamine and 4.5 g of triphenyl phosphine were added to the solution.

The mixture was stirred at room temperature for 15 hours, and the resulting reaction solution was poured into 50 ml of ice balls, adjusted to pH 3, and then separated from the liquid phase. The organic layer was separated, washed with saturated sodium bicarbonate solution and with water.

And dried over MgSO ₄ and concentrated.

The residue was purified by column chromatography on silica gel developed with a developing solvent of benzene-ethyl acetate (3: 1), to obtain 4.5 g (71%) of the present compound of the following structure.

Ir (CHCl ₃ ), ν _max (cm ^-1 ): 1764,1732,1652,1612

(5) (3R, 4R) -4-{(1R) -1-carboxyethoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-triphenyl-phosphoranylidene Preparation of Methyl) azetidin-2-one (Step F)

4.5 g of the product of Reference Example 1 (4) was dissolved in 70 ml of acetone, and then 23 ml of water and 5.7 ml of 1N NaOH solution were added to the solution.

The mixture was stirred at room temperature for 2 hours, and then 2.8 ml of 1N NaOH solution was added, followed by hydrolysis by stirring at Salon for 30 minutes.

The resulting reaction solution was adjusted to pH 7.0, concentrated, and the residue was triturated with isopropyl ether to obtain a powder.

This powder was then suspended in a mixture of 50 ml of water and 50 ml of ethyl acetate.

The suspension was adjusted to pH 2.0 under ice cooling to separate an organic layer, dried over MgSO ₄ , and concentrated to give 4.16 g (96%) of the present compound of the following structure.

(6) (3R, 4R) -4-{(1R) -3 (1-methyl-1H-tetrazol-5-yl) thio-2-oxo-1-methylpropoxy} -3-benzamido- Preparation of 1- (1-diphenyloxycarbonyl_1-triphenylphosphoranylidenemethyl) azetidin-2-one (step of G + H + J)

(i) 3.29 g of the product of Reference Example 1 (5) were dissolved in 40 ml of methylene chloride, and 0.57 ml of N-methylmorpholine and 0.45 ml of ethylchloroformate (C-COOEt) were added to this solution at -10 ° C. It was.

The mixture was reacted at that temperature (-10 占 폚) for 30 minutes while stirring to produce a compound of the following structure.

To the reaction solution containing the above compound was added dropwise 10 ml of ethyl ethyr containing 8 mmole of diazomethine under ice cooling.

After the addition reaction was completed, the mixture was stirred for 30 minutes to produce a diazomethylation reaction, resulting in (3R, 4R) -4-{(1R) -3-diazo-2-oxo-1-methylpropoxy having the following structure: } -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-triphenyl-phosphoranyledenmethyl) azetidin-2-one was obtained.

(ii) 1.43 ml of 6NHCl dioxane solution was added dropwise to the solution obtained in Reference Example 6 (1) under ice cooling. The mixture was stirred for 30 minutes at that temperature (ice-cooled), and the resulting reaction solution was poured into 50 ml of ice water to separate the organic layer, washed with saturated aqueous sodium bicarbonate solution, and then washed with water.

And dried over MgSO ₄ and concentrated to give an oily product (3R, 4R) -4-{(1R) -3-chloro-2-oxo-1-methylpropoxy} -3-benzamido-1- ( 3.10 g of 1-diphenylmethoxycarbonyl-1-triphenyl-phosphoranylidene-methyl) azetidin-2-one were obtained.

(iii) The oily product was dissolved in 50 ml of methylene chloride, and then 0.60 g of 1-methyl-5-mercapto-1H-tetrazole and 0.47 ml of pyridine were added to the solution.

The mixture was stirred at room temperature for 15 hours, whereby chloro group was substituted with (1-methyl-terrazol-5-yl) thio group. The reaction solution thus obtained was injected with 50 ml of ice water to separate the organic layer, and then washed with saturated aqueous sodium bicarbonate solution and washed with water.

And dried over MgSO ₄ and concentrated.

The residue was purified by column chromatography on silica gel developed with benzene-ethyl acetate (2: 1) to give the present compound of the following structure, (3R, 4R) -4-{(1R) -3 (1-methyl). -1H-tetrazol-5-yl) thio-2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenyl-methoxycarbonyl-1-triphenylphosphoranilidene 2.05 g (56%) of methyl) acetidin-2-one was obtained.

In the above formulae, -Tz-Me is a 1-methyl-tetrazol-5-yl group.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1766, 1730, 1653, 1615

Reference Example 2

(1) (3R, 4R) -4-{(1S) -1-ethoxycarbonyl-ethoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-hydroxymethyl ) -Azetidin-2-one

3.0 g of compound (a) obtained in Reference Example 1 (1) was dissolved in 150 ml of methylene chloride, and ozone was passed through this solution until blue color was changed.

1 g of zinc powder and 1 ml of acetic acid were added to the reaction solution at -60 ° C, and the temperature of the mixture was raised to 0 ° C.

At that temperature, 6.8 g of zinc powder and 6.3 ml of acetic acid were added, and the mixture was stirred for 30 minutes.

The reaction mixture thus obtained was filtered to wash the filtrate with saturated aqueous sodium bicarbonate solution and then with water.

And dried over MgSO ₄ and concentrated to give 2.75g (96%) of this Example compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 3420, 1781, 1735,1660,1600

NMR (CDCl ₃ ), δ _ppm : 1.18, 1.21 (3H, t, -CH ₂ CH ₃ ), 1.18, 1.48 (3H, d, -CHCH ₃ ), 4.03, 4.12 (2H, q, -CH ₂ CH ₃ ), 4.33, 4.43 (1H, q-CHCH ₃ ), 4.75, 4.80 (1H, dd, 3-H), 4.90, 4.90, 4.99 (1H, d, 4-H), 5.40, 5.53 (1H, br, s, -CHOH), 6.86, 6.92 (1H, s, -CHph ₃ ), 7.60-7.80 (15H, m, C ₆ H ₅ x 3).

(2) (3R, 4R) -4-{(1S) -1-ethoxycarbonylethoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-chloro-methyl) Preparation of Azetidin-2-one

2.75 g of the product of Reference Example 1 (1) was dissolved in 500 ml of methylene chloride, and after ice-cooling, 1.24 g of pyridine and 1.87 g of thionyl chloride were added to the solution, followed by stirring for 30 minutes.

The reaction solution was poured into ice water to separate the organic layer, washed with saturated sodium bicarbonate solution, and then washed with water.

And dried over MgSO ₄ and concentrated.

Thus, 2.64 g (93%) of this Example compound was obtained.

IR (CHCl ₃ ), ν _max (cm ⁻¹ ): 1785, 1738, 1666,1605.

NMR (CDCl ₃ ), δ _ppm : 1.22 (3H, t, -CH ₂ CH ₃ ), 1.37, 1.47 (3H, d, -CHCH ₃ ), 4.12 (2H, q, -CH ₂ CH ₃ ), 4.44 ( 1H, q-CHCH ₃ ), 4.73 (1H, dd, 3-H), 5.32, 5.37 (1H, d, 4-H), 6.17, 6.21 (1H, br, s, -CHCl), 6.87, 6.92 ( 1H, s, -CHph ₂ ), 7.10-7.70 (15H, m, C ₆ H ₅ x3).

(3) (3R, 4R) -4-{(1S) -1-ethoxycarbonylethoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-triphenyl-force Preparation of Foranilidenemate) -azetidin-2-one

2.64 g of fresh raw material of Reference Example 1 (2) was dissolved in 50 ml of chloroform, and then 0.75 ml of triethylamine and 2.75 g of triphenylphosphine were added to the solution.

This mixture was stirred for 15 hours at room temperature.

The reaction solution was poured into 50 ml of ice water and adjusted to pH 3.

The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, washed with water, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography on silica gel developed with a benzene-ethyl acetate (3: 1) solvent to give 2.50 g (67%) of the present compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1761, 1739, 1655,1615

(4) Preparation of (3R, 4R) -4-{(1S) -1-carboxycarbonyl-1-triphenyl-phosphoranylidenemethyl) azetidin-2-one

2.50 g of the product of Reference Example 1 (3) was dissolved in 37 ml of acetone, and then 12 ml of water and 3.16 ml of 1N NaOH solution were added to the solution.

The mixture was stirred at room temperature for 2 hours, and then 1.6 ml of 1N NaOH aqueous solution was further added.

And it stirred at room temperature for 30 minutes.

The resulting reaction solution was adjusted to pH 7.0, concentrated, and the residue was triturated with isopropyl ether and filtered to obtain a powder.

This powder was then suspended in a mixture of 50 ml of water and 50 ml of ethyl acetate.

This suspension was adjusted to pH 2.0 under ice cooling and the organic layer was separated.

And dried over MgSO ₄ and concentrated to give 2.28g (95%) of this Example compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1765,1730,1658,1617

(1) (3R, 4R) -4 {(1S) -3- (1-methyl-1H-tetrazol-5-yl) thio-2-oxo-1-methylpropoxy} -3-benzamido- Preparation of 1- (1-diphenylmethoxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one

2.10 g of the product of Reference Example 1 (4) were dissolved in 25 ml of methylene chloride, and then added to this solution at 0.36 ml of N-methylphoroline and 0.29 ml -10 ° C of ethylchloroformate.

The mixture was stirred at that temperature for 30 minutes.

To this reaction solution, 10 ml of ethyl ether containing 5.5 m mole of diazomethane was added dropwise under ice cooling.

After completion of the further reaction, the mixture was stirred for 30 minutes to give (3R, 4R) -4-{(1S) -3-diazo-2-oxo-1-methylpropoxy} -3-benzamido-1- The solution which comprises (1-diphenylmethoxycarbonyl-1-triphenylphosphoranilidenemethyl) azetidin-2-one was obtained.

To this solution was added dropwise 0.91 ml of a solution of 6NHCl in dioxane under ice cooling.

The mixture was stirred at that temperature for 30 minutes. The resulting reaction solution was poured into 10 ml of ice water, the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and washed with water.

And dried over MgSO ₄ and concentrated to (3R, 4R) -4-{(1S) -3-chlor-2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenyl 2.05 g of an oil product of methoxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one was obtained.

The oily product was dissolved in 20 ml of methylene chloride, and then 0.32 g of 1-methyl-5-mercapto-1 H-tetrazole and 0.26 ml of pyridine were added to the solution.

Then stirred at room temperature for 15 hours.

The reaction solution was poured into 20 ml of ice water, and the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, and then washed with water.

And dried over MgSO ₄ and concentrated.

The residue was purified by column chromatography on silica gel developed with benzene-ethyl acetate (2: 1) to give the present compound, (3R, 4R) -4-{(1S) -3- (1-methyl-1H -Tetrazol-5-yl) thio-2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-triphenyl phosphoranilidenemethyl) ase 1.70 g (72%) of Tidin-2-one were obtained.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1765,1735,1658,1619

Reference Example 3

(1) (3R, 4R) -4-{(1R) -3-diazo-2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl- Preparation of 1-triphenylphosphoranylidenemethyl-azetidin-2-one

3.29 g of the product of Reference Example 1 (5) was dissolved in 40 ml of methylene chloride, and then 0.57 ml of N-methyllofoline and 0.45 ml of ethylchloroformate were added to this solution at -10 ° C.

This mixture was stirred for 30 min at -10 ° C.

10 ml of ethyl ether containing 8 m mole of diazomethane was added dropwise to the reaction solution under ice-cooling.

After the addition reaction was completed, the mixture was stirred for 30 minutes, and 0.23 ml of acetic acid was added, followed by further stirring for 30 minutes.

The resulting reaction solution was poured into ice water, the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, and then washed with water.

And dried over MgSO ₄ and concentrated.

The residue was purified by column chromatography on silica gel developed with a benzene-ethyl acetate (3: 1) solvent to give 2.91 g (86%) of the present compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 2110,1763, 1665,1618

(2) (3R, 4R) -4 {(1R) -3-chloro-2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxy-carbonyl-1 Preparation of -triphenylphosphoranylidenemethyl-azetidin-2-one

2.91 g of the product of Reference Example 3 (1) was dissolved in 40 ml of methylene chloride, and then 0.92 ml of a solution of 6NHCl in dioxane was added dropwise under ice cooling.

The mixture was stirred at that temperature for 30 minutes.

The resulting reaction solution was poured into 50 ml of ice water, and the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, and then washed with water.

And dried over MgSo ₄ and concentrated to give 2.73g (93%) of this Example compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1765,1742,1650,1618

(3) (3R, 4R) -4-{(1R) -3- (2-methyl-1,3,4-thiadiazol-5-yl) thio-2-oxo-1-methylpropoxy}- Preparation of 3-benzamido-1- (1-diphenylmethoxycarbonyl-1-triphenyl-phosphoranylidenemethyl-azetidin-2-one

1.76 g of the product of Reference Example 3 (2) was dissolved in 30 ml of methylene chloride, and then 0.35 g of 2-methyl-5-mercapto-1,3,4-thiadiazole and 0.26 ml of pyridine were added to the solution.

The mixture was stirred at room temperature for 15 hours and then poured into 30 ml of ice water.

The organic layer was separated, washed with saturated sodium bicarbonate solution and with water.

And dried over MgSO ₄ and concentrated.

The residue was stopped by column chromatography on silica gel developed with benzene-acetylacetate (2: 1) to give 1.40 g (71%) of the present compound.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1763,1737,1652,1615

Reference Example 4

(1) (3R, 4R) -4 {(1S) -1-carboxyethoxy} -3-benzamido-1- (1-diphenylmethoxy-carbonyl-2-methylprop-1-enyl) Preparation of Azetidin-2-one

6.10 g of Compound (a) of Reference Example 1 (1) were dissolved in 70 ml of acetone, and 30 ml of water containing 470 mg of sodium hydroxide was added to the solution under ice-cooling.

The mixture was stirred for 1 hour at its ice cold temperature, then for another hour at room temperature, and the acetone was evaporated.

The resulting aqueous solution was washed with ethyl ether, adjusted to acidic pH value 2.0 and extracted with ethyl acetate.

The organic extract was dried over MgSO ₄ , concentrated and crystallized from ethyl ether to give 5.30 g (91%) of the present compound.

m.p. 172 174 ℃ (decomposition)

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1775, 1724, 1660,1605

NMR (CDCl ₃ ), δ _ppm : 1.40 (3H, dJ = 6.8 Hz, -CHCH ₃ ), 2.01 (3H, s, = CH), 2.23, (3H, s, = CH ₃ ), 4.41 (1H, q , J = 6.8 Hz, -CHCH ₃ ), 4.75 (1H, dd, J = 6.1 Hz, 3-H), 5.14 (1H, s, 4-H), 6.82 (1H, s, -CHpH ₂ ), 6.90 ˜7.80 (15H, m, C ₆ H ₅ x ₃ ).

(2) (3R, 4R) -4-{(1S) -3-diazo-2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenyl methoxy-carbonyl Preparation of -1-methylprop-1-enyl) azetidin-2-one

5.00 g of the product of Reference Example 3 (1) were dissolved in 70 ml of methylene chloride, and then 1.19 ml of N-methylmorpholine and 0.96 ml of ethylchloroformate were added to this solution at -10 ° C.

This mixture was stirred for 30 min at -10 ° C.

40 ml of etherether containing 18 m mole of diazomethane was added dropwise to the reaction solution in ice. After completion of the addition reaction, the mixture was stirred for 30 minutes, and then 0.5 ml of acetic acid was added, followed by stirring for 10 minutes.

The resulting reaction solution was poured into 100 ml of nonaqueous water.

The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and then with water.

And concentrated.

Thus, 5.15 g of this example compound of the following structure was obtained.

IR (CHCl ₄ ), ν _max (cm ^-1 ): 2210,1775,1722,1660

NMR (CDCl ₃ ), δ _ppm : 1.32 (3H, d, J = 6.8 Hz, -CHCH ₃ ), 2.07 (3H, s, = CH ₃ ), 2.28 (3H, s, = CH ₃ ), 4.15 (1H , q, J = 6.8 Hz, -CHCH ₃ ), 4.83 (1H, dd, J = 7.1 Hz, 3-H), 5.04 (1H, d, J = 1Hz, 4-H), 5.30 (1H, s, -CHN ₂ ), 6.88 (1H, s, -CHph ₂ ), 7.10-7.85 (15H, m, C ₆ H ₅ x ₃ ).

(3) (3R, 4R) -4-{(1S) -3-chloro-2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxy-carbonyl- Preparation of 2-methylprop-1-enyl) azetidin-2-one

5.15 g of the product of Reference Example 4 (2) was dissolved in 50 ml of methylene chloride, and then 9 ml of a solution of 1 N HCl in dioxane was added dropwise under cold ice.

The mixture was stirred at that temperature for 30 minutes and then 50 ml of ice water was added thereto.

The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and then with water.

Then, dried over MaSO ₄ and concentrated to obtain 5.10 g of this Example compound having the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1772,1723,1663,1603

NMR (CDCl ₃ ), δ _ppm : 1.34 (3H, d, J = 6.8 Hz, -CHCH ₃ ), 2.04 (3H, s, = -CH ₃ ), 2.27 (3H, s, = CH ₃ ), 4.05 ( 2H, s-CH ₂ Cl), 4.27 (1H, q, J = 6.8 Hz, -CHCH ₃ ), 4.78 (1H, dd, J = 7 Hz, 3-H), 5.06 (1H, d, J = 1 Hz, 4-H), 6.88 (1H, s, -CHph ₃ ), 7.00 -7.90 (15H, m, C ₆ H ₅ x 3).

(4) (3R, 4R) -4-{(1S) -3- (1-methyl-1H-tetrazol-5-yl) thio-2-oxo-1-methylpropoxy} -3-benzamido Preparation of -1- (1-diphenylmethoxy-carbonyl-1-triphenyl-phosphoranylidenemethyl) azetidin-2-one

5.10 g of the product of Reference Example 4 (3) were dissolved in 50 ml of methylene chloride, and then 1.06 g of 1-methyl-5-mercapto-1H-datrazole and 0.9 ml of pyridine were added to the solution.

The mixture was stirred at room temperature for 15 hours and then added to 50 ml of ice water.

The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, washed with water and dried over MaSO ₄ .

And concentrated.

The residue was purified by column chromatography on silica gel developed with benzene-ethyl acetate (3: 1) to give 5.16 g (89%) of the compound of this example in the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1773,1725,1665,1605

NMR (CDCl ₃ ), δ _ppm : 1.35 (3H, d, J = 6.8 Hz, -CHCH ₃ ), 2.20 (3H, s, = CH ₃ ), 2.28 (3H, s, = CH ₃ ), 3.86 (3H , s, tetrazole 1-CH ₃ ), 4.22 (2H, s, -CH ₂ S-), 4.37 (1H, q, J = 6.8 Hz, -CHCH), 4.83 (1H, dd, J = 6.1 Hz, 3-H), 5.21 (1H, d, J = 1 Hz, 4-H), 6.86 (1H, s, -CHph ₂ ), 7.00-7.80 (15H, m, C ₆ H ₅ x 3).

(5) (3R, 4R) -4-{(1S) -3- (1-methyl-1H-tetrazol-5-yl) thio-2-oxo-1-methylpropoxy} -3-benzamido Preparation of -1- (1-diphenylmethoxycarboyl-1-hydroxymethyl) azetidin-2-one

(3R, 4R) -4-{(1S) -3- (1-methyl-1H-tetrazol-5-yl) thio-2-oxo-1-methylpropoxy-3-benzamido-1- ( 2.00 g of 1-diphenylmethoxy-carbonyl-2-methylprop-1-enyl) azetidin-2-one was dissolved in 80 ml of methylene chloride and then -60 ° C with this solution until ozone turned blue. Passed 9 in.

In the resulting solution, 0.40 g of zinc powder and 0.4 ml were added at −60 ° C. to raise the temperature of the mixture to 0 ° C., and then 3.98 g of zinc powder and 3.60 ml of acetic acid were added at that temperature.

The mixture was stirred for 30 minutes.

The reaction mixture thus obtained was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate solution and then with water.

Then, dried over MaSO ₄ and concentrated to obtain 1.10 g (57%) of the present compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ⁻¹ ): 3400,1776,1740,1664,1604.

(6) (3R, 4R) -4-{(1S) -3- (1-methyl-1H-tetrazol-5-yl) thio-2-oxo-1-methylpropoxy} -3-benzamido Preparation of -1- (1-diphenylmethoxycarbonyl-1-chloro- (methyl) azetidan-2-one

After dissolving 1.38 g of the product of Reference Example 4 (5) in 40 ml of methylene chloride, ice-cooling, 0.53 ml of pyridine and 0.48 ml of thionyl chloride were added to the solution, followed by stirring for 15 minutes.

The reaction solution was poured into 50 ml of ice water.

The organic layer was separated, washed with saturated sodium bicarbonate solution, washed with water, dried over MgSO and concentrated.

Thus, 1.21 g (63%) of this Example compound of the following structures was obtained.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1789,1752,1663,1603

(7) (3R, 4R) -4-{(1S) -3 (1-methyl-1H-tetrazol-5-yl) thio-2-oxo-1-methylpropoxy} -3-benzamido- Preparation of 1- (1-diphenylmethoxycarbonyl-1-triphenyl-phosphoranylidenemethyl) azetidin-2-one

1.20 g of the product of Reference Example 4 (6) was dissolved in 40 ml of chloroform, and 0.57 g of triphenylphosphine was added to the solution.

The mixture was stirred at room temperature for 15 minutes, and the reaction solution was washed with saturated aqueous sodium bicarbonate solution, dried over MaSO ₄ and concentrated.

The residue was purified by column chromatography on silica gel developed with benzyl ethyl acetate (2: 1) to obtain 0.86 g (53%) of the present compound.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1765,1735,1658,1619

Reference Example 5

(1) (3R, 4R) -4 {(1S) -3-iodine-2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxy-carbonyl-1 Preparation of -methylprop-1-enyl) azetidin-2-one

1.32 g of the product of Reference Example 3 (3) was dissolved in 30 ml of acetone, and 0.98 g of sodium iodide was added to this solution.

The mixture was stirred for 20 minutes at room temperature and then concentrated.

The residue was dissolved in 20 ml of ethyl acetate, and then the solution was washed with aqueous sodium thiosulfate solution and washed with water.

Then, dried over MgSO ₄ and concentrated to give 1.32 g (86%) of the present compound of the following structure.

NMR (CDCl ₃ ), δ _ppm : 1.40 (3H, d, J = 6.8Hz, -CH ₂ CH ₃ ), 2.07 (3H, s, CH ₃ ), 2.30 (3H, s, = CH ₃ ), 3.56 3.76 (2H, Bq, J = 10 Hz, -CH ₂ I), 4.44 (1H, q, J = 6.8 Hz, -CHCH ₃ ), 4.83 (1H, dd, J = 7, 1 Hz, 3-H), 5.08 ( 1H, d, J = 1 Hz, 4-H, 6.90 (1H, s, -CHph ₃ ), 7.00-9.90 (15H, m, C ₆ H ₅ x 3).

(2) (3R, 4R) -4-{(1S) -oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-methylpropru-1- Preparation of enyl) azetidin-2-one

1.32 g of the product of Reference Example 1 (1) was dissolved in 15 ml of methylene chloride, and the solution was mixed with 3.12 g of zinc powder and 2.9 ml of acetic acid under ice cooling, and the resulting mixture was stirred at that temperature for 30 minutes.

Thus, the reaction mixture thus obtained was filtered to wash the filtrate with saturated aqueous sodium bicarbonate solution and with water.

And dried over MgSO ₄ and concentrated.

The residue was purified by column chromatography on silica gel developed with benzene-ethyl acetate (4: 1) to give 0.75 g (70%) of the present compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1771,1723,1665,1604

NMR (CDCl ₃ ), δ _ppm : 1.28 (3H, d, J = 7 Hz, -CHCH ₃ ), 1.90 (3H, s, -COCH ₃ ), 2.03 (3H, s, = CH ₃ ), 2.25 (3H, s, = CH ₃ ), 4.17 (1H, q, J = 7Hz, -CHCH ₂ ), 4.79 (1H, dd, J = 7Hz, 3-H), 5.01 (1H, d, J = 1Hz, 4-H ), 6.87 (1H, s, -CHph ₃ ), 7.00-7.80 (15H, m, C ₆ H ₅ x3).

(3) (3R, 4R) -4-{(1S) -2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-hydrocy- Preparation of 1-methyl) azetidin-2-one

210 mg of the product of Reference Example 5 (2) was dissolved in 15 ml of methylene chloride and ozone was passed through this solution until ozone turned blue.

To this reaction solution, 50 mg of zinc powder and 0.05 mg of acetic acid were added at -60 ° C to raise the temperature of the mixed solution to 0 ° C, and then 510 mg of zinc powder and 0.05 ml of acetic acid were further added.

The resulting mixture was stirred at that temperature for 30 minutes and then filtered.

The filtrate was washed with saturated aqueous sodium bicarbonate solution and washed with water.

And dried over MgSO ₄ and concentrated.

The residue was purified by column chromatography on silica gel to give 115 mg (57%) of this Example compound of the following structure.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 3450,1780,1745,1724,1663

NMR (CDCl ₃ ), δ _ppm : 1.17, 1.38 (3H, d, -CHCH ₃ ), 2.00, 2.04 (3H, s, -COCH ₃ ), 4.03, 4.45 (1H, q, -CHCH ₃ ), 4.75, 4.70 (1H, dd, 3-H), 4.76, 4.94 (1H, q, 4-H), 5.30,45.40 (1H, br, s, -CHOH), 6.68, 6.90 (1H, s, -CHph ₃ ) , 7.00-7.80 (15H, m, C ₆ H ₅ x3).

(4) (3R, 4R) -4-{(1S) -2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-chloromethyl) Preparation of Azetidine-2-one

115 mg of the product of Reference Example 5 (3) was dissolved in 2 ml of methylene chloride and ice-cooled, and 32 µl of pyridine and 32 µl of thionyl chloride were added to the solution.

Then it stirred at that temperature for 30 minutes.

This reaction solution was poured into ice water.

The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and washed with water.

And dried over MgSO ₄ and concentrated.

Thus, 109 g (92%) of this Example compound were obtained.

NMR (CDCl ₃ ), δ _ppm : 1.26, 1.28 (3H, d, -CHCH ₃ ), 1.96 (3H, s, = CH ₃ ), 2.08 (3H, s, = CH ₃ ), 4.22, 4.25 (1H, q-CHCH ₃ ), 4.67, 4.72 (1H, dd, 3-H), 5.31, 5.47, (1H, d, 4-H), 6.25 (1H, s, -CHC), 6.83, 6.87 (1H, s , -CHph ₃ ), 7.00-7.80 (15H, m, C ₆ H ₅ x 3.)

(5) (3R.4R) -4-{(1S) -2-oxo-1-methylpropoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-1-triphenyl- Preparation of Phosphoranilidenemethyl) azetidin-2-one

After dissolving 195 mg of the product of Reference Example 5 (4) in 50 ml of chloroform, 44 mg of triethylamine and 190 mg of triphenyl phosphine were added to this solution.

This mixture was stirred for 15 hours at room temperature.

The reaction solution was poured into ice water, and the organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, and washed with water.

And dried over MgSO ₄ and concentrated.

This residue was purified by column chromatography on silica gel to give 144 ng (53%) of the present compound.

IR (CHCl ₃ ), ν _max (cm ^-1 ): 1763,1720,1660,1625

Reference Example 6

(1) (3R, 4R) -4-{(1R) -2-1-ethoxycarbonyl-ethoxy} -3-benzamido-1- (1-diphenylmethoxycarbonyl-2-methyl Preparation of Prop-1-enyl) azetidin-2-one

(1R, 5S) -3-phenyl-6- (1-diphenylmethoxy-carbonyl-2-methylprop-1-enyl) -7-oxa-4-oxa used in Reference Example 1 (1) 1.0 ml of -2.6.-diazabicyclo [3,2,0] hepto-2-ene, 35 ml of L-(+)-lactic acid ethyl ester instead of the DL-α-lactic acid ethyl ester used in Reference Example 1 (1) Dissolved in.

0.5 ml of trifluoromethinesulfonic acid was added to the resultant solution.

The mixture was stirred at room temperature for 1.5 hours.

The reaction solution thus obtained was added to 200 ml of an aqueous sodium bicarbonate solution and ice-cooled for 30 minutes.

The aqueous layer was removed, an oil product was taken, dissolved in 70 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and then washed with water.

And dried over MgSO ₄ and concentrated.

The residue was purified by column chromatography on silica gel developed with benzene-ethyl acetate (7: 1) and crystallized from ethyl ether.

Thus, 4.3 g (34%) of this Example compound, ie, the compound (a) of Reference Example 1 (1), was obtained.

This product yielded higher yields than Reference Example 1 (1).

Claims (7)

The 7-amino group of the following general formula (II) 2-alkyl-7-amino-1-oxa-1-dethia-3-cepem compound is anhydrous, and the carboxylic acid of the following general formula (III) in an inert organic solvent Acylation to yield the 7-N-acylated product of formula (I ') followed by the departure of the carboxyl protecting group from the 7-N-acylated product of formula (I') A process for preparing the 7-acylamino-2-alkyl-1-oxa-1-decia-3-cefem compound of formula (I) and a pharmaceutically acceptable salt or ester thereof.

Where R represents a group of the general formula

(Wherein R ₁ is a 2-thienyl group or 3-thienyl group, R ₂ is a hydrogen atom or a carboxyl group) The group of the following general formula is shown.

Wherein R ₃ is a hydrogen atom, a lower alkyl or a carboxyl lower alkyl group R ₄ is a hydrogen atom or a methoxy group, R ₅ is a lower alkyl group, R ₆ is a tetrazolyl thiomethyl group or methyltetrazolyl thiomethyl group. A 'is a carboxyl protecting group. The 7-acylamino-2-alkyl-1-oxa-1-dec according to claim 1, wherein the carboxylic acid of general formula (III) is thienyl-substituted carboxylic acid of general formula (III '). A method for preparing a thia-3-cefem compound and a pharmaceutically acceptable salt or ester thereof.

Wherein R ₂ is a hydrogen atom or an acid halide, acid anhydride, mixed acid anhydride, active ester or active azide between carboxyl group or stomach carboxyl. The 7-acylamino-2-alkyl-1-oxa-1-dec according to claim 1, wherein the carboxylic acid of general formula (III) is a thiazolyl-substituted carboxylic acid of general formula (III '). A method for preparing a thia-3-cefem compound and a pharmaceutically acceptable salt or ester thereof.

Wherein R ₃ is a hydrogen atom, a lower alkyl group or a carboxyl-lower alkyl group, or an acid halide, acid anhydride, mixed acid anhydride, active ester or active azide of the above carboxylic acid. The 7-acylamino-2-alkyl-1-oxa-1-dethia according to claim 1, wherein the inert organic solvent is selected from ethyl acetate, methylene chloride, tetrahydrofuran, dimethylform amide and acetnitrile. -3-cefem compound and pharmaceutically acceptable salts or esters thereof. The 7-acylamino-2-alkyl-1-oxa-1-decia-3-cefem compound according to claim 1, wherein the acylation reaction is carried out at a reflux temperature of the reaction solvent. Process for preparing acceptable salts or esters thereof. The 7-acylamino-2-alkyl-1-oxa-1-dethia-3-cepem compound and pharmaceutically acceptable compound according to claim 1, wherein the acylation reaction is carried out in the presence of an acylation catalyst. Process for the preparation of salts or esters thereof. The azetidinone compound of the following general formula (XVII ') is cyclized to produce a cefem compound of the following general formula (XVIII'), and R ₈ CO is _released from the 7α-amino group of the compound (XVIII ') by a known method. Leaving the group to give a compound of the formula (XIX ') and reacting the compound (XI X') with an aromatic aldehyde to form a compound in the form of a Schiff base type compound of formula (XX) The Scheme base-modified 7α-amino group of (XX) is subjected to stericinversion or steric translocation reaction by α-methoxylation at the 7 position of compound (XX) to generate the following general formula (XXIII) The Schiff base component R ₉ -CH = is separated from compound (XXIII) in a conventional manner, and the carboxyl protecting group (A ′) is separated from the resulting compound. 2-alkyl-1-oxa-1-dethia-cephalosporin compound Method.

In the above formula, R ₄ is a hydrogen atom or a methoxy group, R ₅ is a lower alkyl group, R ₇ is a methyl group or halomethyl group or tetrazolyl thiomethyl group or methyltetrazolylthio methyl group, A is a hydrogen atom or a carboxyl protecting group. R ₆ CO- group is an acyl group, ph is a phenyl group and A 'is a carboxyl protecting group. R ₉ is an aromatic group.